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Wang Z, Mierxiati A, Zhu W, Li T, Xu H, Wan F, Ye D. FOXA1-dependent NSUN2 facilitates the advancement of prostate cancer by preserving TRIM28 mRNA stability in a m5C-dependent manner. NPJ Precis Oncol 2025; 9:127. [PMID: 40319192 PMCID: PMC12049421 DOI: 10.1038/s41698-025-00904-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 04/06/2025] [Indexed: 05/07/2025] Open
Abstract
RNA epigenetics is gaining increased attention for its role in the initiation, metastasis, and drug resistance of tumors. These studies have primarily focused on m6A modification. However, despite being the second most abundant modification found in RNA, the role of m5C modification in prostate cancer remains largely unexplored. Here, we predict an RNA m5C methyltransferase, NSUN2, as a potential therapeutic target for prostate cancer using various bioinformatics approaches, and verify the potential of NSUN2 as a target through multiple preclinical models. Mechanistically, NSUN2 enhances the stability of TRIM28 mRNA by adding m5C modification, promoting the expression of TRIM28. Concurrently, FOXA1, a prostate cancer lineage-specific transcription factor, transcriptionally activates the expression of NSUN2. Our study confirms the clinical potential of targeting RNA epigenetics for the treatment of prostate cancer and elucidates, mechanistically, how RNA epigenetics participates in the complex biological activities within tumors via the FOXA1-NSUN2-TRIM28 axis.
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Affiliation(s)
- Zhenda Wang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | | | - Wenkai Zhu
- Department of Urology, First People's Hospital of Kashi, Kashi, China
| | - Tian Li
- Tianjin Medical University, Tianjin, China.
| | - Hua Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Fangning Wan
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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2
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Fang T, Liu L, Sun H, Zhang X, Sun X, Yu Z, Gong L, Xie S, Zhao Y, Li Y, Qiu L, An G, He B, Hao M. A novel indirubin- 3-monoxime derivative I3MV- 8b exhibits remarkable cytotoxicity against multiple myeloma by targeting TRIM28. Biomark Res 2025; 13:57. [PMID: 40197552 PMCID: PMC11978164 DOI: 10.1186/s40364-025-00773-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
INTRODUCTION Maintaining protein homeostasis is vital for multiple myeloma (MM) cell survival. Indirubin- 3-monoxime (I3MO), a potential MM therapeutic, inhibits proteasome activity, while histone deacetylase 6 (HDAC6) regulates autophagy. We developed I3MV- 8b, an I3MO derivative, integrating an HDAC6 inhibitor moiety to enhance dual inhibition of proteasome and autophagy pathways. METHODS The anti-MM effects of I3MV- 8b were tested in vitro and in vivo. To identify downstream targets, RNA-seq and dual-luciferase reporter assays were performed. Additionally, ChIP-seq and IP-MS techniques were employed to elucidate the underlying molecular mechanism. RESULTS I3MV- 8b significantly suppressed MM cell proliferation and induced apoptosis. Combined with proteasome inhibitors, I3MV- 8b enhanced cytotoxicity by concurrently inhibiting proteasome and autophagy pathways. It reduced TRIM28 transcription, correlating with lower expression of proteasome subunits and autophagy-related genes. ChIP-seq revealed that TRIM28 binds to proteasome gene promoters, and its knockdown decreased proteasome subunit expression and activity. TRIM28 knockdown also impaired autophagosome formation. IP-MS and Co-IP assays showed TRIM28 interacted with 14-3 - 3ζ, a negative regulator of autophagy, promoting its ubiquitination and degradation. This interaction reduced autophagy regulation, further sensitizing cells to treatment. CONCLUSIONS I3MV- 8b offers a novel dual inhibition strategy targeting proteasome and autophagy, presenting a promising therapeutic option for MM.
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Affiliation(s)
- Teng Fang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Lanting Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Hao Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiaoyu Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiyue Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Zhen Yu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Lixin Gong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Shiyi Xie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yonglong Zhao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Yan Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China
| | - Lugui Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Department of Hospital Management, Gobroad Healthcare Group, Beijing, China
| | - Gang An
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
- Department of Hospital Management, Gobroad Healthcare Group, Beijing, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
| | - Mu Hao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Department of Hospital Management, Gobroad Healthcare Group, Beijing, China.
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Matsuhisa K, Sato S, Kaneko M. Identification of E3 Ubiquitin Ligase Substrates Using Biotin Ligase-Based Proximity Labeling Approaches. Biomedicines 2025; 13:854. [PMID: 40299435 PMCID: PMC12024899 DOI: 10.3390/biomedicines13040854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 04/30/2025] Open
Abstract
Ubiquitylation is a post-translational modification originally identified as the first step in protein degradation by the ubiquitin-proteasome system. Ubiquitylation is also known to regulate many cellular processes without degrading the ubiquitylated proteins. Substrate proteins are specifically recognized and ubiquitylated by ubiquitin ligases. It is necessary to identify the substrates for each ubiquitin ligase to understand the physiological and pathological roles of ubiquitylation. Recently, a promiscuous mutant of a biotin ligase derived from Escherichia coli, BioID, and its variants have been utilized to analyze protein-protein interaction. In this review, we summarize the current knowledge regarding the molecular mechanisms underlying ubiquitylation, BioID-based approaches for interactome studies, and the application of BirA and its variants for the identification of ubiquitin ligase substrates.
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Affiliation(s)
- Koji Matsuhisa
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore;
| | - Shinya Sato
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan;
| | - Masayuki Kaneko
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan;
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Zhang L, Wang X, Hu D, Li S, Sun M, Liu Q, Feng H, Zhou M, Chen C, Zhou H, Ma S. SUMOylation facilitates the stability of BCR-ABL to promote chronic myeloid leukemia progression. Oncogene 2025:10.1038/s41388-025-03350-y. [PMID: 40148689 DOI: 10.1038/s41388-025-03350-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 01/19/2025] [Accepted: 03/11/2025] [Indexed: 03/29/2025]
Abstract
Tyrosine kinase inhibitors (TKIs) targeting the oncoprotein BCR-ABL have improved the prognosis for patients with chronic myeloid leukemia (CML). However, TKI resistance and persistent expression of BCR-ABL are responsible for the relapse and progression of CML. Here, we describe a novel approach to induce BCR-ABL protein degradation by small ubiquitin-like modifier (SUMO) modification. The E3 SUMO ligase TRIM28, upregulated during the progression of CML, promoted SUMOylation of BCR-ABL, thereby inhibiting its binding to the autophagy receptor P62 and repressing its autophagic degradation. Accordingly, genetic and pharmacological inhibition of TRIM28 or SUMOylation suppressed progression in both the CML mouse model and patient-derived xenograft model. Furthermore, targeting SUMOylation of BCR-ABL restrained the proliferation of TKI-resistant CML cells. These results identify the mechanism by which TRIM28 maintains BCR-ABL stability to promote CML progression and suggest SUMOylation as a target for CML treatment.
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Affiliation(s)
- Lu Zhang
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xuefeng Wang
- National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Key Laboratory of Innovative Drug Pharmaceutical Research and Clinical Evaluation Jointly Established Disciplines in Anhui Province, Hefei, China
| | - Dongmei Hu
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shijie Li
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mingshan Sun
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qian Liu
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huimin Feng
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Minran Zhou
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chunyan Chen
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Huan Zhou
- National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
- Key Laboratory of Innovative Drug Pharmaceutical Research and Clinical Evaluation Jointly Established Disciplines in Anhui Province, Hefei, China.
| | - Sai Ma
- Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
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5
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Jang SH, Choi HW, Ahn J, Jang S, Yoon JH, Lee MG, Chi SG. XAF1 antagonizes TRIM28 activity through the assembly of a ZNF313-mediated destruction complex to suppress tumor malignancy. MOLECULAR BIOMEDICINE 2024; 5:58. [PMID: 39532800 PMCID: PMC11557793 DOI: 10.1186/s43556-024-00224-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible pro-apoptotic protein that is commonly inactivated in multiple human cancers. Nevertheless, the molecular basis for its tumor suppression function remains largely uncharacterized. Here we report that XAF1 antagonizes the oncogenic activity of tripartite motif containing 28 (TRIM28) ubiquitin E3 ligase through zinc finger protein 313 (ZNF313)-induced ubiquitination and proteasomal degradation. XAF1 exerts apoptosis-promoting effect more strongly in TRIM28+/+ versus XAF1-/- tumor cells and suppresses tumor cell growth, migration, invasion, and epithelial-to-mesenchymal transition and xenograft tumor growth in a highly TRIM28-dependent fashion. Mechanistically, XAF1 interacts directly with the RING domains of TRIM28 and ZNF313 through the ZF6 and ZF7 domain, respectively, thereby facilitating ZNF313 interaction with and ubiquitination of TRIM28. A mutant XAF1 lacking either ZF6 or ZF7 domain exhibits no activity to promote TRIM28 ubiquitination. By destabilizing TRIM28, XAF1 blocks TRIM28-driven ubiquitination of p53 and RLIM, p53-HDAC1 interaction, and TWIST1 stabilization. Intriguingly, TRIM28 destabilizes XAF1 through K48-linked polyubiquitination and proteasomal degradation to protect tumor cells from apoptotic stress, indicating its role as an intrinsic antagonist against XAF1 and the antagonistic interplay of XAF1 and TRIM28. XAF1 expression is inversely correlated with TRIM28 expression in cancer cell lines and tumor tissues and more tightly associated with the survival of TRIM28-high versus TRIM28-low patients. Together, this study uncovers a novel mechanism by which XAF1 suppresses tumor malignancy and an important role for XAF1-TRIM28 interplay in governing stress response, illuminating the mechanistic consequence of its alteration during tumorigenic process.
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Affiliation(s)
- Seung-Hun Jang
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Hwi-Wan Choi
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Jieun Ahn
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Sungchan Jang
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Ji-Hye Yoon
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Min-Goo Lee
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Sung-Gil Chi
- Department of Life Sciences, Korea University, Seoul, 02841, Republic of Korea.
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Maghsoudloo M, Mokhtari K, Jamali B, Gholamzad A, Entezari M, Hashemi M, Fu J. Multifaceted role of TRIM28 in health and disease. MedComm (Beijing) 2024; 5:e790. [PMID: 39534556 PMCID: PMC11554878 DOI: 10.1002/mco2.790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 09/28/2024] [Accepted: 09/28/2024] [Indexed: 11/16/2024] Open
Abstract
The TRIM (tripartite motif) family, with TRIM28 as a key member, plays a vital role in regulating health and disease. TRIM28 contains various functional domains essential for transcriptional regulation, primarily through its interaction with KRAB-ZNF proteins, which influence chromatin remodeling and gene expression. Despite extensive research, the precise mechanisms by which TRIM28 impacts health and disease remain elusive. This review delves into TRIM28's multifaceted roles in maintaining health, contributing to a variety of diseases, and influencing cancer progression. In cancers, TRIM28 exhibits a dual nature, functioning as both a tumor promoter and suppressor depending on the cellular context and cancer type. The review also explores its critical involvement in processes such as DNA repair, cell cycle regulation, epithelial-to-mesenchymal transition, and the maintenance of stem cell properties. By uncovering TRIM28's complex roles across different cancers and other diseases, this review underscores its potential as a therapeutic target. The significance of TRIM28 as a versatile regulator opens the door to innovative therapeutic strategies, particularly in cancer treatment and the management of other diseases. Ongoing research into TRIM28 may yield key insights into disease progression and novel treatment options.
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Affiliation(s)
- Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncologythe Research Center for Preclinical MedicineSouthwest Medical UniversityLuzhouSichuanChina
| | - Khatere Mokhtari
- Department of Cellular and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Behdokht Jamali
- Department of Microbiology and GeneticKherad Institute of Higher EducationBusheherIran
| | - Amir Gholamzad
- Farhikhtegan Medical Convergence Sciences Research CenterFarhikhtegan Hospital Tehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research CenterFarhikhtegan Hospital Tehran Medical SciencesIslamic Azad UniversityTehranIran
- Department of GeneticsFaculty of Advanced Science and TechnologyTehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research CenterFarhikhtegan Hospital Tehran Medical SciencesIslamic Azad UniversityTehranIran
- Department of GeneticsFaculty of Advanced Science and TechnologyTehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncologythe Research Center for Preclinical MedicineSouthwest Medical UniversityLuzhouSichuanChina
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Xu H, Wang T, Nie H, Sun Q, Jin C, Yang S, Chen Z, Wang X, Tang J, Feng Y, Sun Y. USP36 promotes colorectal cancer progression through inhibition of p53 signaling pathway via stabilizing RBM28. Oncogene 2024; 43:3442-3455. [PMID: 39343961 PMCID: PMC11573713 DOI: 10.1038/s41388-024-03178-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality globally and p53, a widely recognized tumor suppressor, contributes to the development of CRC. Ubiquitin-specific protease 36 (USP36), belonging to the deubiquitinating enzyme family, is involved in tumor progression across multiple cancers. However, the underlying molecular mechanism in which USP36 regulates p53 signaling pathway in CRC is unclear. Here, our study revealed that USP36 was increased in CRC tissues and associated with unfavorable prognosis. Functionally, elevated USP36 could promote proliferation, migration, and invasion of CRC cells in vitro and in vivo. Mechanistically, USP36 could interact with and stabilize RBM28 via deubiquitination at K162 residue. Further, upregulated RBM28 could bind with p53 to suppress its transcriptional activity and therefore inactivate p53 signaling pathway. Collectively, our investigation identified the novel USP36/RBM28/p53 axis and its involvement in promoting cell proliferation and metastasis in CRC, which presents a promising therapeutic strategy for CRC treatment.
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Affiliation(s)
- Hengjie Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Tuo Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Hongxu Nie
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Qingyang Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Chi Jin
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Sheng Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Zhihao Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Xiaowei Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Junwei Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
- The Colorectal Institute of Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China.
| | - Yifei Feng
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
- The Colorectal Institute of Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China.
| | - Yueming Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
- The Colorectal Institute of Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China.
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Huang S, Li X. UBE2C promotes LUAD progression by ubiquitin-dependent degradation of p53 to inactivate the p53/p21 signaling pathway. Discov Oncol 2024; 15:589. [PMID: 39448441 PMCID: PMC11502638 DOI: 10.1007/s12672-024-01465-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
Lung adenocarcinoma (LUAD) is one of the greatest causes of cancer death worldwide. As a novel potential tumor biomarker, ubiquitin-conjugating enzyme E2C (UBE2C) is a critical factor during the onset and development of human cancers. However, the mechanisms of UBE2C in LUAD are not well understood. In this study, increased expression level of UBE2C was observed in LUAD tumor tissues. High LUAD level portended a worse prognosis of LUAD patients. Down-regulation of UBE2C attenuated the cell proliferation and cycle, migration, and invasion. Consistently, the tumorigenic capacity of LUAD cells in nude mice was significantly suppressed by the knockdown of UBE2C. Knockdown of UBE2C inhibited the degradation of p53 protein via an ubiquitin-proteasome pathway, thereby increasing p53 and p21 protein expression. Moreover, the inhibition of LUAD cell malignant phenotypes caused by UBE2C knockdown was attenuated on account of the inactivation of p53/p21 signaling pathway. In conclusion, UBE2C facilitates cell malignant behaviour in LUAD by ubiquitin-dependent degradation of p53 to suppress the p53/p21 signaling pathway. UBE2C is potentially developed as a therapeutic target for patients with LUAD.
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Affiliation(s)
- Siyuan Huang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China
| | - Xingya Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China.
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9
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Chiang DC, Yap BK. TRIM25, TRIM28 and TRIM59 and Their Protein Partners in Cancer Signaling Crosstalk: Potential Novel Therapeutic Targets for Cancer. Curr Issues Mol Biol 2024; 46:10745-10761. [PMID: 39451518 PMCID: PMC11506413 DOI: 10.3390/cimb46100638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Aberrant expression of TRIM proteins has been correlated with poor prognosis and metastasis in many cancers, with many TRIM proteins acting as key oncogenic factors. TRIM proteins are actively involved in many cancer signaling pathways, such as p53, Akt, NF-κB, MAPK, TGFβ, JAK/STAT, AMPK and Wnt/β-catenin. Therefore, this review attempts to summarize how three of the most studied TRIMs in recent years (i.e., TRIM25, TRIM28 and TRIM59) are involved directly and indirectly in the crosstalk between the signaling pathways. A brief overview of the key signaling pathways involved and their general cross talking is discussed. In addition, the direct interacting protein partners of these TRIM proteins are also highlighted in this review to give a picture of the potential protein-protein interaction that can be targeted for future discovery and for the development of novel therapeutics against cancer. This includes some examples of protein partners which have been proposed to be master switches to various cancer signaling pathways.
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Affiliation(s)
| | - Beow Keat Yap
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang 11800, Malaysia
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10
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Lin KH, Hibbert JE, Flynn CG, Lemens JL, Torbey MM, Steinert ND, Flejsierowicz PM, Melka KM, Lindley GT, Lares M, Setaluri V, Wagers AJ, Hornberger TA. Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis. EMBO Rep 2024; 25:3812-3841. [PMID: 39143258 PMCID: PMC11387408 DOI: 10.1038/s44319-024-00227-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/19/2024] [Accepted: 07/26/2024] [Indexed: 08/16/2024] Open
Abstract
Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discover that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Interestingly, different from the role reported in a previous study based on C2C12 myoblasts, multiple lines of both in vitro and in vivo evidence reveal that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 are not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discover that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.
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Affiliation(s)
- Kuan-Hung Lin
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Jamie E Hibbert
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Corey Gk Flynn
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Jake L Lemens
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Melissa M Torbey
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Nathaniel D Steinert
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Philip M Flejsierowicz
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Kiley M Melka
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Garrison T Lindley
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
| | - Marcos Lares
- Department of Dermatology, University of Wisconsin - Madison, Madison, WI, USA
| | | | - Amy J Wagers
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Joslin Diabetes Center, Boston, MA, USA
| | - Troy A Hornberger
- Department of Comparative Biosciences, University of Wisconsin - Madison, Madison, WI, USA.
- School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA.
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11
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Cuinat S, Quélin C, Effray C, Dubourg C, Le Bouar G, Cabaret-Dufour AS, Loget P, Proisy M, Sauvestre F, Sarreau M, Martin-Berenguer S, Beneteau C, Naudion S, Michaud V, Arveiler B, Trimouille A, Macé P, Sigaudy S, Glazunova O, Torrents J, Raymond L, Saint-Frison MH, Attié-Bitach T, Lefebvre M, Capri Y, Bourgon N, Thauvin-Robinet C, Tran Mau-Them F, Bruel AL, Vitobello A, Denommé-Pichon AS, Faivre L, Brehin AC, Goldenberg A, Patrier-Sallebert S, Perani A, Dauriat B, Bourthoumieu S, Yardin C, Marquet V, Barnique M, Fiorenza-Gasq M, Marey I, Tournadre D, Doumit R, Nugues F, Barakat TS, Bustos F, Jaillard S, Launay E, Pasquier L, Odent S. Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective. J Med Genet 2024; 61:824-832. [PMID: 38849204 PMCID: PMC11420740 DOI: 10.1136/jmg-2024-109854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 05/19/2024] [Indexed: 06/09/2024]
Abstract
INTRODUCTION Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.
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Affiliation(s)
- Silvestre Cuinat
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
| | - Chloé Quélin
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Pontchaillou, CHU Rennes, Rennes, France
| | - Claire Effray
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
| | - Christèle Dubourg
- Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
| | - Gwenaelle Le Bouar
- Unité de Médecine fœtale, Service de Gynécologie-Obstétrique, CHU Rennes, Rennes, France
| | | | - Philippe Loget
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Pontchaillou, CHU Rennes, Rennes, France
| | - Maia Proisy
- Radiology Department, CHU de Brest, Brest, France
| | - Fanny Sauvestre
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
| | - Mélie Sarreau
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
| | - Sophie Martin-Berenguer
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
- Department of Gynaecology and Obstetrics, Mother and Children's Hospital, CHU Limoges, Limoges, France
| | - Claire Beneteau
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
| | - Sophie Naudion
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
| | - Vincent Michaud
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Benoit Arveiler
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Aurélien Trimouille
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Pierre Macé
- Institut méditerranéen d'imagerie médicale appliquée à la gynécologie, la grossesse et l'enfance IMAGE2, Marseille, France
| | - Sabine Sigaudy
- Département de Génétique Médicale, Hôpital Timone Enfant, AP-HM, Marseille, France
| | - Olga Glazunova
- Département de Génétique Médicale, Hôpital Timone Enfant, AP-HM, Marseille, France
| | - Julia Torrents
- Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, AP-HM, Marseille, France
| | - Laure Raymond
- Genetics Department, Laboratoire Eurofins Biomnis, Lyon, France
| | | | - Tania Attié-Bitach
- Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, AP-HP, Paris, France
- INSERM UMR 1163, Imagine Institute, Université Paris Cité, Paris, France
| | - Mathilde Lefebvre
- Service de Pathologie fœtale, Hôpital Universitaire Armand Trousseau, AP-HP, Paris, France
| | - Yline Capri
- Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France
| | - Nicolas Bourgon
- Service d'Obstétrique-Maternité Chirurgie, Médecine et Imagerie foetales, AP-HP, Hopital Universitaire Necker-Enfants Malades, Paris, France
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
| | - Christel Thauvin-Robinet
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
- Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, Dijon, France
| | - Frédéric Tran Mau-Them
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Ange-Line Bruel
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Antonio Vitobello
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Anne-Sophie Denommé-Pichon
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Laurence Faivre
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, Dijon, France
| | - Anne-Claire Brehin
- Department of Pathology, Department of Genetics and Reference Center for Developmental Abnormalities, F-76000, CHU de Rouen, Rouen, France
- Inserm U1245, Université de Rouen Normandie, Rouen, France
| | - Alice Goldenberg
- Inserm U1245, Université de Rouen Normandie, Rouen, France
- Department of Genetics and Reference Center for Developmental Abnormalities, F-76000, CHU de Rouen, Rouen, France
| | | | - Alexandre Perani
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Benjamin Dauriat
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Sylvie Bourthoumieu
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
- UMR 7252, CNRS, XLIM, F-87000, Université de Limoges, Limoges, France
| | - Catherine Yardin
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
- UMR 7252, CNRS, XLIM, F-87000, Université de Limoges, Limoges, France
| | - Valentine Marquet
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Marion Barnique
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Maryse Fiorenza-Gasq
- Department of Gynaecology and Obstetrics, Mother and Children's Hospital, CHU Limoges, Limoges, France
| | - Isabelle Marey
- INSERM U1209, Institute for Advanced Bioscience, Université Grenoble Alpes, Grenoble, France
| | - Danielle Tournadre
- CPDPN de Grenoble, Echographie obstétricale dépistage et diagnostic, CHU Grenoble Alpes, Grenoble, France
| | - Raïa Doumit
- Service d'Imagerie Pédiatrique, CHU Grenoble Alpes, Grenoble, France
| | - Frédérique Nugues
- Service d'Imagerie Pédiatrique, CHU Grenoble Alpes, Grenoble, France
| | - Tahsin Stefan Barakat
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Francisco Bustos
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
| | - Sylvie Jaillard
- Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
- EHESP, INSERM U1085 IRSET, Université de Rennes 1, Rennes, France
| | - Erika Launay
- Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
| | - Laurent Pasquier
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
- FHU GenoMeds, ERN ITHACA, CHU Rennes, Rennes, France
| | - Sylvie Odent
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
- FHU GenoMeds, ERN ITHACA, CHU Rennes, Rennes, France
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12
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Yao Y, Zhou S, Yan Y, Fu K, Xiao S. The tripartite motif-containing 24 is a multifunctional player in human cancer. Cell Biosci 2024; 14:103. [PMID: 39160596 PMCID: PMC11334367 DOI: 10.1186/s13578-024-01289-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/15/2024] [Indexed: 08/21/2024] Open
Abstract
Tripartite motif-containing 24 (TRIM24), also known as transcriptional intermediary factor 1α (TIF1α), is the founding member of TIF1 family. Recent evidence indicates that aberrant expression of TRIM24, functions as an oncogene, is associated with poor prognosis across various cancer types. TRIM24 exhibits a multifaceted structure comprising an N-terminal TRIM region with a RING domain, B-box type 1 and type 2 domains, and a coiled-coil region, as well as a C-terminal plant-homeodomain (PHD)-bromodomain. The bromodomain serves as a 'reader' of epigenetic histone marks, regulating chromatin structure and gene expression by linking associated proteins to acetylated nucleosomal targets, thereby controlling transcription of genes. Notably, bromodomains have emerged as compelling targets for cancer therapeutic development. In addition, TRIM24 plays specialized roles as a signal transduction molecule, orchestrating various cellular signaling cascades in cancer cells. Herein, we review the recent advancements in understanding the functions of TRIM24, and demonstrate the research progress in utilizing TRIM24 as a target for cancer therapy.
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Affiliation(s)
- Yuanbing Yao
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China
| | - Sheng Zhou
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China
- Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yue Yan
- Yanbian University Medical School, Yanji, Jilin, China
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- Center MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, 87# Xiangya Road, Changsha, 410008, Hunan, China.
| | - Shuai Xiao
- The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, 69# Chuanshan Road, Hengyang, 421001, Hunan, China.
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13
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Liu F, Chen J, Li K, Li H, Zhu Y, Zhai Y, Lu B, Fan Y, Liu Z, Chen X, Jia X, Dong Z, Liu K. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer 2024; 23:148. [PMID: 39048965 PMCID: PMC11270804 DOI: 10.1186/s12943-024-02046-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/15/2024] [Indexed: 07/27/2024] Open
Abstract
Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.
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Affiliation(s)
- Fangfang Liu
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Jingyu Chen
- Department of Pediatric Medicine, School of Third Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Kai Li
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Haochen Li
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yiyi Zhu
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yubo Zhai
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Bingbing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yanle Fan
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Ziyue Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Xiaojie Chen
- School of Basic Medicine, Henan University of Science and Technology, Luoyang, China
| | - Xuechao Jia
- Henan International Joint Laboratory of TCM Syndrome and Prescription in Signaling, Traditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Zigang Dong
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
| | - Kangdong Liu
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
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14
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Li K, Wang H, Jiang B, Jin X. TRIM28 in cancer and cancer therapy. Front Genet 2024; 15:1431564. [PMID: 39100077 PMCID: PMC11294089 DOI: 10.3389/fgene.2024.1431564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 07/01/2024] [Indexed: 08/06/2024] Open
Abstract
TRIM28 (tripartite motif protein 28) was initially believed to be a transcription inhibitor that plays an important role in DNA damage repair (DDR) and in maintaining cancer cellular stemness. As research has continued to deepen, several studies have found that TRIM28 not only has ubiquitin E3 ligase activity to promote degradation of substrates, but also can promote SUMOylation of substrates. Although TRIM28 is highly expressed in various cancer tissues and has oncogenic effects, there are still a few studies indicating that TRIM28 has certain anticancer effects. Additionally, TRIM28 is subject to complex upstream regulation. In this review, we have elaborated on the structure and regulation of TRIM28. At the same time, highlighting the functional role of TRIM28 in tumor development and emphasizing its impact on cancer treatment provides a new direction for future clinical antitumor treatment.
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Affiliation(s)
- Kailang Li
- Department of Oncology and Hematology, Beilun District People’s Hospital, Ningbo, China
| | - Haifeng Wang
- Department of Oncology and Hematology, Beilun District People’s Hospital, Ningbo, China
| | - Bitao Jiang
- Department of Oncology and Hematology, Beilun District People’s Hospital, Ningbo, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo, China
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15
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Yu J, Zhao Y, Xie Y. Advances of E3 ligases in lung cancer. Biochem Biophys Rep 2024; 38:101740. [PMID: 38841185 PMCID: PMC11152895 DOI: 10.1016/j.bbrep.2024.101740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/02/2024] [Accepted: 05/23/2024] [Indexed: 06/07/2024] Open
Abstract
Lung cancer is a leading cause of cancer-related death, and the most common type of lung cancer is non-small cell lung cancer, which accounts for approximately 85 % of lung cancer diagnoses. Recent studies have revealed that ubiquitination acts as a crucial part of the development and progression of lung cancer. The E1-E2-E3 three-enzyme cascade has a core function in ubiquitination, so targeted adjustments of E3 ligases could be used in lung cancer treatment. Hence, we elucidate research advances in lung cancer-related E3 ligases by briefly describing the structure and categorization of E3 ligases. Here, we provide a detailed review of the mechanisms by which lung cancer-related E3 ligases modify substrate proteins and regulate signaling pathways to facilitate or suppress cancer progression. We hope to show a new perspective on targeted precision therapy for lung cancer.
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Affiliation(s)
- Jingwen Yu
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, PR China
| | - Yiqi Zhao
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, PR China
| | - Yue Xie
- Liaoning Academy of Chinese Medicine, Liaoning University Traditional Chinese Medicine, Shenyang, Liaoning, PR China
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16
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Huang Z, Dong J, Guo T, Jiang W, Hu R, Zhang S, Du T, Jiang X. TRIM28 Regulates Proliferation of Gastric Cancer Cells Partly Through SRF/IDO1 Axis. J Cancer 2024; 15:4417-4429. [PMID: 38947391 PMCID: PMC11212089 DOI: 10.7150/jca.95094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 05/14/2024] [Indexed: 07/02/2024] Open
Abstract
Background: Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important molecule that affects the occurrence and development of tumors, but its function in GC has not been elucidated clearly. The purpose of this study is to explore the molecular mechanism by which TRIM28 affect the GC. Methods: TRIM28 expression was tested in RNA-seq data from TCGA database, tumor tissue samples from patients and GC cell lines. Genes were silenced or overexpressed by siRNA, lentivirus-mediated shRNA, or plasmids. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to explore the proliferation of GC cells after TRIM28 knockdown. RNA-seq and TCGA database were used to identify target genes. Luciferase report assay was employed to detect the possible mechanism between TRIM28 and Indoleamine 2,3-dioxygenase (IDO1). Tryptophan concentration in cell supernatant was measured using a fluorometric assay kit. MGC-803 and 746T cells were injected into mice to establish xenograft animal models. Results: The expression of TRIM28 was positively correlated with tumor size and poorer prognosis. Upregulation of TRIM28 was observed in GC tissues and cells. In vitro, we proved that knockdown of TRIM28 significantly inhibited the proliferation of GC cells. Then TRIM28 was found to be positively correlated with the expression of IDO1 in GC cells. In accordance with this, tryptophan levels in cell supernatants were increased in TRIM28 knockdown GC cells and overexpression of IDO1 could reverse this phenotype. Serum response factor (SRF), a reported regulator of IDO1, was also regulated by TRIM28 in GC cells. And decreased expression of IDO1 induced by TRIM28 knockdown could be partly reversed through overexpression of serum response factor (SRF) in GC cells. Functional research demonstrated that the expression of IDO1 was increased in GC and IDO1 knockdown could also inhibited the proliferation of GC cells. Furthermore, overexpression of IDO1 could partly reverse proliferation inhibited by TRIM28 knockdown in GC cells. In vivo, knockdown of TRIM28 significantly inhibited the tumor growth and overexpression of IDO1 and SRF both could reverse proliferation inhibited by TRIM28 knockdown. Conclusions: TRIM28 is crucial in the development of GC, and may regulate IDO1 through SRF. TRIM28 promote GC cell proliferation through SRF/IDO1 axis.
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Affiliation(s)
- Zhiye Huang
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Jiaxing Dong
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Taohua Guo
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Wanju Jiang
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Renhao Hu
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Shun Zhang
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Tao Du
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Xiaohua Jiang
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
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Jeong IH, Yun JK, Jin JO, Hong JH, Lee JY, Lee GD, Lee PCW. E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression. Cell Oncol (Dordr) 2024; 47:819-832. [PMID: 37910276 DOI: 10.1007/s13402-023-00896-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2023] [Indexed: 11/03/2023] Open
Abstract
PURPOSE Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy. METHODS We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells. RESULTS We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway. CONCLUSION Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer.
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Affiliation(s)
- In-Ho Jeong
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jae Kwang Yun
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jun-O Jin
- Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jeong Hee Hong
- Department of Physiology, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea
| | - Ji Yeon Lee
- Division of Rheumatology, Department of Medicine, Seoul St. Mary's Hospital, Catholic University, Seoul, 06591, Korea.
| | - Geun Dong Lee
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
- Lung Cancer Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
- Lung Cancer Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
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Yang Y, Zhang Y, Chen G, Sun B, Luo F, Gao Y, Feng H, Li Y. KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m 6A reader YTHDC1 protein degradation. J Exp Clin Cancer Res 2024; 43:141. [PMID: 38745192 PMCID: PMC11092262 DOI: 10.1186/s13046-024-03040-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/08/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Neuroblastoma (NB) patients with amplified MYCN often face a grim prognosis and are resistant to existing therapies, yet MYCN protein is considered undruggable. KAP1 (also named TRIM28) plays a crucial role in multiple biological activities. This study aimed to investigate the relationship between KAP1 and MYCN in NB. METHODS Transcriptome analyses and luciferase reporter assay identified that KAP1 was a downstream target of MYCN. The effects of KAP1 on cancer cell proliferation and colony formation were explored using the loss-of-function assays in vitro and in vivo. RNA stability detection was used to examine the influence of KAP1 on MYCN expression. The mechanisms of KAP1 to maintain MYCN mRNA stabilization were mainly investigated by mass spectrum, immunoprecipitation, RIP-qPCR, and western blotting. In addition, a xenograft mouse model was used to reveal the antitumor effect of STM2457 on NB. RESULTS Here we identified KAP1 as a critical regulator of MYCN mRNA stability by protecting the RNA N6-methyladenosine (m6A) reader YTHDC1 protein degradation. KAP1 was highly expressed in clinical MYCN-amplified NB and was upregulated by MYCN. Reciprocally, KAP1 knockdown reduced MYCN mRNA stability and inhibited MYCN-amplified NB progression. Mechanistically, KAP1 regulated the stability of MYCN mRNA in an m6A-dependent manner. KAP1 formed a complex with YTHDC1 and RNA m6A writer METTL3 to regulate m6A-modified MYCN mRNA stability. KAP1 depletion decreased YTHDC1 protein stability and promoted MYCN mRNA degradation. Inhibiting MYCN mRNA m6A modification synergized with chemotherapy to restrain tumor progression in MYCN-amplified NB. CONCLUSIONS Our research demonstrates that KAP1, transcriptionally activated by MYCN, forms a complex with YTHDC1 and METTL3, which in turn maintain the stabilization of MYCN mRNA in an m6A-dependent manner. Targeting m6A modification by STM2457, a small-molecule inhibitor of METTL3, could downregulate MYCN expression and attenuate tumor proliferation. This finding provides a new alternative putative therapeutic strategy for MYCN-amplified NB.
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Affiliation(s)
- Yi Yang
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China
| | - Yingwen Zhang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Guoyu Chen
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Bowen Sun
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Fei Luo
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yijin Gao
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China
| | - Haizhong Feng
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Yanxin Li
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China.
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Chen M, Shi P, Wang P, Zhang T, Zhao J, Zhao L. Up-regulation of Trim28 in pregnancy-induced hypertension is involved in the injury of human umbilical vein endothelial cells through the p38 signaling pathway. Histol Histopathol 2024; 39:603-610. [PMID: 37522419 DOI: 10.14670/hh-18-651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
AIMS The present study is to analyze the regulation and potential molecular mechanism of Trim28 on vascular endothelial injury induced by pregnancy-induced hypertension (PIH). METHODS Trim28 mRNA in placental tissues and peripheral blood from PIH patients were determined by quantitative real-time polymerase chain reaction. The serum from PIH was used to stimulate human umbilical vein endothelial cells (HUVECs). After silencing Trim28 in HUVECs, we used CCK-8 assay, Transwell assay and flow cytometry to investigate proliferation, migration and apoptosis. Western blotting was used to measure Trim28 protein level and p38 phosphorylation level. After addition of p38 inhibitor, the proliferation, migration and apoptosis of HUVECs with silenced Trim28 were studied again. RESULTS Trim28 expression in placental tissues and peripheral blood from PIH patients is elevated, and serum from these patients can up-regulate the expression of Trim28 in HUVECs in vitro. Trim28 silencing significantly inhibits the proliferation and migration of HUVECs by affecting the cell cycle. Down-regulation of Trim28 expression promotes the apoptosis of HUVECs. Trim28 regulates the biological function of HUVECs by affecting the activity of the p38 signaling pathway. CONCLUSIONS The present study demonstrates that Trim28 is up-regulated in peripheral blood of patients with PIH and participates in HUVECs injury through the p38 signaling pathway.
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Affiliation(s)
- Min Chen
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China
| | - Peng Shi
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China
| | - Ping Wang
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China
| | - Tingting Zhang
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China
| | - Jing Zhao
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China
| | - Li Zhao
- Department of Obstetrics and Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, PR China.
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Wang B, Hu H, Wang X, Shao Z, Shi D, Wu F, Liu J, Zhang Z, Li J, Xia Z, Liu W, Wu Q. POLE2 promotes osteosarcoma progression by enhancing the stability of CD44. Cell Death Discov 2024; 10:177. [PMID: 38627379 PMCID: PMC11021398 DOI: 10.1038/s41420-024-01875-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 04/19/2024] Open
Abstract
Osteosarcoma (OS) is the most prevalent primary malignancy of bone in children and adolescents. It is extremely urgent to develop a new therapy for OS. In this study, the GSE14359 chip from the GEO database was used to screen differentially expressed genes in OS. DNA polymerase epsilon 2 (POLE2) was confirmed to overexpress in OS tissues and cell lines by immunohistochemical staining, qPCR and Western blot. Knockdown of POLE2 inhibited the proliferation and migration of OS cells in vitro, as well as the growth of tumors in vivo, while the apoptosis rate was increased. Bioinformatics analysis revealed that CD44 and Rac signaling pathway were the downstream molecule and pathway of POLE2, which were inhibited by knockdown of POLE2. POLE2 reduced the ubiquitination degradation of CD44 by acting on MDM2. Moreover, knockdown of CD44 inhibited the tumor-promoting effects of POLE2 overexpression on OS cells. In conclusion, POLE2 augmented the expression of CD44 via inhibiting MDM2-mediated ubiquitination, and then activated Rac signaling pathway to influence the progression of OS, indicating that POLE2/CD44 might be potential targets for OS treatment.
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Affiliation(s)
- Baichuan Wang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Hongzhi Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Xiaohui Wang
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Deyao Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Fashuai Wu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Jianxiang Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Zhicai Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Juan Li
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China
| | - Zhidao Xia
- Institute of Life Sciences 2, Swansea University Medical School, Singleton Park, Swansea, SA2 8PP, UK
| | - Weijian Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China.
| | - Qiang Wu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, China.
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Wei S, Xing J, Chen J, Chen L, Lv J, Chen X, Li T, Yu T, Wang H, Wang K, Yu W. DCAF13 inhibits the p53 signaling pathway by promoting p53 ubiquitination modification in lung adenocarcinoma. J Exp Clin Cancer Res 2024; 43:3. [PMID: 38163876 PMCID: PMC10759521 DOI: 10.1186/s13046-023-02936-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Lung cancer is a malignant tumor with the highest mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to be contributed to lung cancer progression with deleterious effects. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role in lung cancer remains unknown. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in lung adenocarcinoma (LUAD). METHODS So as to investigate the effect of DCAF13 on lung adenocarcinoma cell function using in vivo and in vitro. Mechanistically, we have identified the downstream targets of DCAF13 by using RNA-sequencing, as well as ubiquitination assays, co-immunoprecipitation, immunofluorescence, immunohistochemistry and chromatin immunoprecipitation - qPCR experiments. RESULTS Our findings reveal that DCAF13 is a carcinogenic factor in LUAD, as it is highly expressed and negatively correlated with clinical outcomes in LUAD patients. Through RNA-sequencing, it has been shown that DCAF13 negatively regulates the p53 signaling pathway and inhibits p53 downstream targets including p21, BAX, FAS, and PIDD1. We also demonstrate that DCAF13 can bind to p53 protein, leading to K48-linked ubiquitination and degradation of p53. Functionally, we have shown that DCAF13 knockdown inhibits cell proliferation and migration. Our results highlight the significant role of DCAF13 in promoting LUAD progression by inhibiting p53 protein stabilization and the p53 signaling pathway. Furthermore, our findings suggest that high DCAF13 expression is a poor prognostic indicator in LUAD, and DCAF13 may be a potential therapeutic target for treating with this aggressive cancer. CONCLUSIONS The DCAF13 as a novel negative regulator of p53 to promote LUAD progression via facilitating p53 ubiquitination and degradation, suggesting that DCAF13 might be a novel biomarker and therapeutical target for LUAD.
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Affiliation(s)
- Shan Wei
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Jing Xing
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Jia Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Liping Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Jiapei Lv
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Xiaofei Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Tang Li
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Tao Yu
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Huaying Wang
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China
| | - Kai Wang
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, People's Republic of China
| | - Wanjun Yu
- Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China.
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Lin KH, Hibbert JE, Lemens JL, Torbey MM, Steinert ND, Flejsierowicz PM, Melka KM, Lares M, Setaluri V, Hornberger TA. The role of satellite cell-derived TRIM28 in mechanical load- and injury-induced myogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.20.572566. [PMID: 38187693 PMCID: PMC10769277 DOI: 10.1101/2023.12.20.572566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discovered that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Unexpectedly, multiple lines of both in vitro and in vivo evidence revealed that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 were not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discovered that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.
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Affiliation(s)
- Kuan-Hung Lin
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Jamie E. Hibbert
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Jake L. Lemens
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Melissa M. Torbey
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Nathaniel D. Steinert
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Philip M. Flejsierowicz
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Kiley M. Melka
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
| | - Marcos Lares
- Department of Dermatology, University of Wisconsin - Madison, WI, USA
| | | | - Troy A. Hornberger
- Department of Comparative Biosciences, University of Wisconsin - Madison, WI, USA
- School of Veterinary Medicine, University of Wisconsin - Madison, WI, USA
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Li C, Li Y, Wang W, Scimeca M, Melino G, Du R, Shi Y. Deer antlers: the fastest growing tissue with least cancer occurrence. Cell Death Differ 2023; 30:2452-2461. [PMID: 37864097 PMCID: PMC10733395 DOI: 10.1038/s41418-023-01231-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 10/22/2023] Open
Abstract
Deer antlers are a bony organ solely able to acquired distinct unique attributes during evolution and all these attributes are against thus far known natural rules. One of them is as the fastest animal growing tissue (2 cm/day), they are remarkably cancer-free, despite high cell division rate. Although tumor-like nodules on the long-lived castrate antlers in some deer species do occur, but they are truly benign in nature. In this review, we tried to find the answer to this seemingly contradictory phenomenon based on the currently available information and give insights into possible clinic application. The antler growth center is located in its tip; the most intensive dividing cells are resident in the inner layer of reserve mesenchyme (RM), and these cells are more adopted to osteosarcoma rather than to normal bone tissues in gene expression profiles but acquire their energy mainly through aerobic oxidative phosphorylation pathway. To counteract propensity of neoplastic transformation, antlers evolved highly efficient apoptosis exactly in the RM, unparalleled by any known tissues; and annual wholesale cast to jettison the corps. Besides, some strong cancer suppressive genes including p53 cofactor genes and p53 regulator genes are highly positively selected by deer, which would have certainly contributed to curb tumorigenesis. Thus far, antler extracts and RM cells/exosomes have been tried on different cancer models either in vitro or in vivo, and all achieved positive results. These positive experimental results together with the anecdotal folklore that regular consumption of velvet antler is living with cancer-free would encourage us to test antlers in clinic settings.
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Affiliation(s)
- Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Yan Li
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Wenying Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Manuel Scimeca
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
| | - Rui Du
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China.
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, Suzhou, China.
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Ning T, Zhao M, Zhang N, Wang Z, Zhang S, Liu M, Zhu S. TRIM28 suppresses cancer stem-like characteristics in gastric cancer cells through Wnt/β-catenin signaling pathways. Exp Biol Med (Maywood) 2023; 248:2210-2218. [PMID: 38058023 PMCID: PMC10903244 DOI: 10.1177/15353702231211970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/23/2023] [Indexed: 12/08/2023] Open
Abstract
The influences of TRIM28 on the gastric tumorigenesis together with potential molecular mechanisms remain to be studied. We aimed at exploring the important effects of TRIM28 on gastric cancer (GC) and uncovering underling molecular mechanisms. Through immunohistochemistry analysis of 20 pairs of GC and the peritumoral tissues, the expression level of TRIM28 was determined. A variety of assays were applied to explore the important roles of TRIM28 in GC. Western blotting and qRT-PCR analyses were used to analyze the association between TRIM28 and the Wnt/β-catenin signaling pathway. TRIM28 was highly expressed in GC tissues than peritumoral tissues. And high expression level of TRIM28 in GC was associated with good prognostic effects. In vitro functional assays suggested TRIM28 knockdown enhanced the proliferation and clone formation of GC cell. Moreover, TRIM28 knockdown enhanced the expression level of stemness markers, strengthened sphere-forming and drug-resistance properties of GC cells, suggesting important effect on GC cell stemness. Besides, our analysis showed that the Wnt/β-catenin signaling was involved in the effect of TRIM28 on GC cell stemness property, and blocking Wnt/β-catenin signaling pathway obviously rescued the promotion influence of TRIM28 knockdown. Overall, TRIM28 has an important influence on regulating the stem-like property of GC cell via Wnt/β-catenin signaling, suggesting TRIM28 a promising drug target and a potential predictor of prognosis.
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Affiliation(s)
- Tingting Ning
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Mengran Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Nan Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Zhaoqing Wang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Mo Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
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Li K, Xia Y, He J, Wang J, Li J, Ye M, Jin X. The SUMOylation and ubiquitination crosstalk in cancer. J Cancer Res Clin Oncol 2023; 149:16123-16146. [PMID: 37640846 DOI: 10.1007/s00432-023-05310-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND The cancer occurrence and progression are largely affected by the post-translational modifications (PTMs) of proteins. Currently, it has been shown that the relationship between ubiquitination and SUMOylation is highly complex and interactive. SUMOylation affects the process of ubiquitination and degradation of substrates. Contrarily, SUMOylation-related proteins are also regulated by the ubiquitination process thus altering their protein levels or activity. Emerging evidence suggests that the abnormal regulation between this crosstalk may lead to tumorigenesis. PURPOSE In this review, we have discussed the study of the relationship between ubiquitination and SUMOylation, as well as the possibility of a corresponding application in tumor therapy. METHODS The relevant literatures from PubMed have been reviewed for this article. CONCLUSION The interaction between ubiquitination and SUMOylation is crucial for the occurrence and development of cancer. A greater understanding of the crosstalk of SUMOylation and ubiquitination may be more conducive to the development of more selective and effective SUMOylation inhibitors, as well as a promotion of synergy with other tumor treatment strategies.
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Affiliation(s)
- Kailang Li
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Yongming Xia
- Department of Oncology, Yuyao People's Hospital of Zhejiang, Yuyao, 315400, Zhejiang, China
| | - Jian He
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jie Wang
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jingyun Li
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Meng Ye
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
| | - Xiaofeng Jin
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
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Chen Y, Pang J, Liao W, Wan W, Kang T, Gan X, Lin P, Wen D, He Y, Yang H. Overexpression of TRIM28 predicts an unfavorable prognosis and promotes the proliferation and migration of hepatocellular carcinoma. ONCOLOGIE 2023; 25:481-494. [DOI: 10.1515/oncologie-2023-0118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Abstract
Objectives
Previous studies have shown that tripartite motif-containing 28 (TRIM28) might be a latent target for cancer therapy. However, the detailed roles and mechanisms of TRIM28 in hepatocellular carcinoma (HCC) remain ambiguous.
Methods
We systematically analyzed TRIM28 mRNA expression and protein levels in HCC tissues based on large-scale data and publicly available immunohistochemistry images. We estimated the prognostic capacity of TRIM28 in HCC. Additionally, we performed gene enrichment, immune infiltration, and drug sensitivity analyses to further explore the roles of TRIM28 in HCC. To determine the effect of TRIM28 expression on HCC cell proliferation and migration, successful transfection of siRNAs was conducted in MHCC97-L and Huh7 cells, followed by cell functional assays.
Results
We verified the overexpression of TRIM28 in HCC at the mRNA and protein levels. The summary receiver operating characteristics curve with the area under curve of 0.84 (95 % CI: 0.81–0.87) indicated the high accuracy of increasing TRIM28 expression for discriminating HCC from non-HCC tissues. According to The Cancer Genome Atlas datasets, TRIM28 mRNA expression was significantly related to age, grade, stage, and pathologic T (p<0.05). Increased TRIM28 expression levels were significant correlated to poor survival in HCC patients. An enrichment analysis suggested that TRIM28-reated genes primarily participated in the spliceosome signaling pathway, with hub genes including SNRPA1, SNRPF, SNRPD1, SF3B2, SNRPB, SNRPE, and EFTUD2. TRIM28 expression was correlated with the infiltration of five immune cells. Higher TRIM28 expression was linked to better sensitivity of tumor cells to pluripotin. Molecular docking showed that pluripotin could bind to TRIM28. Further, knockdown of TRIM28 inhibited the proliferation and migration of HCC cells.
Conclusions
TRIM28 is highly expressed in HCC and contribute to the proliferation and migration of HCC cells, leading to unfavorable outcomes. These findings indicate TRIM28 promise as a novel prognostic indicator.
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Affiliation(s)
- Yuji Chen
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Jinshu Pang
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Wei Liao
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Weijun Wan
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Tong Kang
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Xiangyu Gan
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Peng Lin
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Dongyue Wen
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Yun He
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
| | - Hong Yang
- Department of Medical Ultrasound , The First Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi Zhuang Autonomous Region , China
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Zheng J, Miao F, Wang Z, Ma Y, Lin Z, Chen Y, Kong X, Wang Y, Zhuang A, Wu T, Li W. Identification of MDM2 as a prognostic and immunotherapeutic biomarker in a comprehensive pan-cancer analysis: A promising target for breast cancer, bladder cancer and ovarian cancer immunotherapy. Life Sci 2023; 327:121832. [PMID: 37276911 DOI: 10.1016/j.lfs.2023.121832] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 06/07/2023]
Abstract
BACKGROUND The murine double minute 2 (MDM2) gene is a crucial factor in the development and progression of various cancer types. Multiple rigorous scientific studies have consistently shown its involvement in tumorigenesis and cancer progression in a wide range of cancer types. However, a comprehensive analysis of the role of MDM2 in human cancer has yet to be conducted. METHODS We used various databases, including TIMER2.0, TCGA, GTEx and STRING, to analyze MDM2 expression and its correlation with clinical outcomes, interacting genes and immune cell infiltration. We also investigated the association of MDM2 with immune checkpoints and performed gene enrichment analysis using DAVID tools. RESULTS The pan-cancer MDM2 analysis found that MDM2 expression and mutation status were observably different in 25 types of cancer tissue compared with healthy tissues, and prognosis analysis showed that there was a significant correlation between MDM2 expression and patient prognosis. Furthermore, correlation analysis showed that MDM2 expression was correlated with tumor mutational burden, microsatellite instability and drug sensitivity in certain cancer types. We found that there was an association between MDM2 expression and immune cell infiltration across cancer types, and MDM2 inhibitors might enhance the effect of immunotherapy on breast cancer, bladder cancer and ovarian cancer. CONCLUSIONS The first systematic pan-cancer analysis of MDM2 was conducted, and it demonstrated that MDM2 was a reliable prognostic biomarker and was closely related to cancer immunity, providing a potential immunotherapeutic target for breast cancer, bladder cancer and ovarian cancer.
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Affiliation(s)
- Jialiang Zheng
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Fenglin Miao
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhao Wang
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yuan Ma
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhenhang Lin
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yaqin Chen
- Nursing Department of Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China
| | - Xu Kong
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yue Wang
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Aobo Zhuang
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Ting Wu
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
| | - Wengang Li
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
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Chen Z, Song J, Xie L, Xu G, Zheng C, Xia X, Lu F, Ma X, Zou F, Jiang J, Wang H. N6-methyladenosine hypomethylation of circGPATCH2L regulates DNA damage and apoptosis through TRIM28 in intervertebral disc degeneration. Cell Death Differ 2023; 30:1957-1972. [PMID: 37438603 PMCID: PMC10406905 DOI: 10.1038/s41418-023-01190-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/31/2023] [Accepted: 06/29/2023] [Indexed: 07/14/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of noncoding RNAs that have been found to be involved in intervertebral disc degeneration (IVDD) progression, and N6-methyladenosine (m6A) broadly exists in circRNAs. Here, we identified circGPATCH2L with a low m6A methylation level to be upregulated in degenerative nucleus pulposus tissues. Mechanistically, as a protein decoy for tripartite motif containing 28 (TRIM28) within aa 402-452 region, circGPATCH2L abrogates the phosphorylation of TRIM28 and inhibits P53 degradation, which contributes to DNA damage accumulation and cellular apoptosis and leads to IVDD progression. Moreover, m6A-methylated circGPATCH2L is recognised and endoribonucleolytically cleaved by a YTHDF2-RPL10-RNase P/MRP complex to maintain the physiological state of nucleus pulposus cells. Thus, our data show the physiological significance of m6A modification in regulating circRNA abundance and provide a potentially effective therapeutic target for the treatment of IVDD.
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Affiliation(s)
- Zhenhao Chen
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Jian Song
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Lin Xie
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Guangyu Xu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Chaojun Zheng
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Xinlei Xia
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Feizhou Lu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200000, China
| | - Xiaosheng Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China
| | - Fei Zou
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China.
| | - Jianyuan Jiang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China.
| | - Hongli Wang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China.
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Zhou GYJ, Zhao DY, Yin TF, Wang QQ, Zhou YC, Yao SK. Proteomics-based identification of proteins in tumor-derived exosomes as candidate biomarkers for colorectal cancer. World J Gastrointest Oncol 2023; 15:1227-1240. [PMID: 37546562 PMCID: PMC10401461 DOI: 10.4251/wjgo.v15.i7.1227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/28/2023] [Accepted: 05/25/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second leading cause of cancer-related death, with high morbidity worldwide. There is an urgent need to find reliable diagnostic biomarkers of CRC and explore the underlying molecular mechanisms. Exosomes are involved in intercellular communication and participate in multiple pathological processes, serving as an important part of the tumor microenvironment. AIM To investigate the proteomic characteristics of CRC tumor-derived exosomes and to identify candidate exosomal protein markers for CRC. METHODS In this study, 10 patients over 50 years old who were diagnosed with moderately differentiated adenocarcinoma were recruited. We paired CRC tissues and adjacent normal intestinal tissues (> 5 cm) to form the experimental and control groups. Purified exosomes were extracted separately from each tissue sample. Data-independent acquisition mass spectrometry was implemented in 8 matched samples of exosomes to explore the proteomic expression profiles, and differentially expressed proteins (DEPs) were screened by bioinformatics analysis. Promising exosomal proteins were verified using parallel reaction monitoring (PRM) analysis in 10 matched exosome samples. RESULTS A total of 1393 proteins were identified in the CRC tissue group, 1304 proteins were identified in the adjacent tissue group, and 283 proteins were significantly differentially expressed between them. Enrichment analysis revealed that DEPs were involved in multiple biological processes related to cytoskeleton construction, cell movement and migration, immune response, tumor growth and telomere metabolism, as well as ECM-receptor interaction, focal adhesion and mTOR signaling pathways. Six differentially expressed exosomal proteins (NHP2, OLFM4, TOP1, SAMP, TAGL and TRIM28) were validated by PRM analysis and evaluated by receiver operating characteristic curve (ROC) analysis. The area under the ROC curve was 0.93, 0.96, 0.97, 0.78, 0.75, and 0.88 (P < 0.05) for NHP2, OLFM4, TOP1, SAMP, TAGL, and TRIM28, respectively, indicating their good ability to distinguish CRC tissues from adjacent intestinal tissues. CONCLUSION In our study, comprehensive proteomic profiles were obtained for CRC tissue exosomes. Six exosomal proteins, NHP2, OLFM4, TOP1, SAMP, TAGL and TRIM28, may be promising diagnostic markers and effective therapeutic targets for CRC, but further experimental investigation is needed.
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Affiliation(s)
- Ge-Yu-Jia Zhou
- Department of Gastroenterology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing 100029, China
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Dong-Yan Zhao
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Teng-Fei Yin
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Qian-Qian Wang
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Yuan-Chen Zhou
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Ma X, Jia S, Wang G, Liang M, Guo T, Du H, Li S, Li X, Huangfu L, Guo J, Xing X, Ji J. TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance. Signal Transduct Target Ther 2023; 8:246. [PMID: 37357254 DOI: 10.1038/s41392-023-01450-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 04/06/2023] [Accepted: 04/25/2023] [Indexed: 06/27/2023] Open
Abstract
Immune checkpoint blockade (ICB) offers a new opportunity for treatment for gastric cancer (G.C.). Understanding the upstream regulation of immune checkpoints is crucial to further improve the efficacy of ICB therapy. Herein, using the CRISPR-Cas9-based genome-wide screening, we identified TRIM28 as one of the most significant regulators of PD-L1, a checkpoint protein, in G.C. cells. Mechanistically, TRIM28 directly binds to and stabilizes PD-L1 by inhibiting PD-L1 ubiquitination and promoting PD-L1 SUMOylation. Furthermore, TRIM28 facilitates K63 polyubiquitination of TBK1, activating TBK1-IRF1 and TBK1-mTOR pathways, resulting in enhanced PD-L1 transcription. It was found that TRIM28 was positively correlated with PD-L1 in G.C. cells. Moreover, high TRIM28 expression suggests poor survival in a cohort of 466 patients with G.C., and this observation is consistent while analyzing data from publicly available databases. Ectopic TRIM28 expression facilitated tumor growth, increased PD-L1 expression, and suppressed T cell activation in mice. Administration of the PD-L1 or TBK1 inhibitor significantly alleviated the TRIM28-induced tumor progression. Furthermore, combining the TBK1 inhibitor with CTLA4 immune checkpoint blockade has synergistic effects on G.C., and provides a novel strategy for G.C. therapy.
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Affiliation(s)
- Xiaoxiao Ma
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Shuqin Jia
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Gangjian Wang
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Min Liang
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ting Guo
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Hong Du
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Sisi Li
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaomei Li
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Longtao Huangfu
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China.
| | - Xiaofang Xing
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
| | - Jiafu Ji
- Department of Gastrointestinal Cancer Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
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Song T, Lv S, Ma X, Zhao X, Fan L, Zou Q, Li N, Yan Y, Zhang W, Sun L. TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. J Biol Chem 2023; 299:104621. [PMID: 36935008 PMCID: PMC10141522 DOI: 10.1016/j.jbc.2023.104621] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss-of-function of TRIM28, a multi-function protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28-TFE3-KDM6A signal axis which plays a critical role in kidney cancer cell autophagy and proliferation.
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Affiliation(s)
- Tanjing Song
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Suli Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Xianyun Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Li Fan
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China
| | - Qingli Zou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Neng Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Yingying Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Wen Zhang
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China
| | - Lidong Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Yang Y, Tan S, Han Y, Huang L, Yang R, Hu Z, Tao Y, Oyang L, Lin J, Peng Q, Jiang X, Xu X, Xia L, Peng M, Wu N, Tang Y, Li X, Liao Q, Zhou Y. The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials. Front Oncol 2023; 13:1100134. [PMID: 36756159 PMCID: PMC9899900 DOI: 10.3389/fonc.2023.1100134] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023] Open
Abstract
Tripartite motif-containing 28 (TRIM28) belongs to tripartite motif (TRIM) family. TRIM28 not only binds and degrades its downstream target, but also acts as a transcription co-factor to inhibit gene expression. More and more studies have shown that TRIM28 plays a vital role in tumor genesis and progression. Here, we reviewed the role of TRIM28 in tumor proliferation, migration, invasion and cell death. Moreover, we also summarized the important role of TRIM28 in tumor stemness sustainability and immune regulation. Because of the importance of TRIM28 in tumors, TIRM28 may be a candidate target for anti-tumor therapy and play an important role in tumor diagnosis and treatment in the future.
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Affiliation(s)
- Yiqing Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Lisheng Huang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,University of South China, Hengyang, Hunan, China
| | - Ruiqian Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,University of South China, Hengyang, Hunan, China
| | - Zifan Hu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,University of South China, Hengyang, Hunan, China
| | - Yi Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,University of South China, Hengyang, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xiaoling Li
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,*Correspondence: Yujuan Zhou, ; Qianjin Liao, ; Xiaoling Li,
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Translational Radiation Oncology, Changsha, Hunan, China,*Correspondence: Yujuan Zhou, ; Qianjin Liao, ; Xiaoling Li,
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Translational Radiation Oncology, Changsha, Hunan, China,*Correspondence: Yujuan Zhou, ; Qianjin Liao, ; Xiaoling Li,
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Pérez-Rodríguez D, Penedo MA, Rivera-Baltanás T, Peña-Centeno T, Burkhardt S, Fischer A, Prieto-González JM, Olivares JM, López-Fernández H, Agís-Balboa RC. MiRNA Differences Related to Treatment-Resistant Schizophrenia. Int J Mol Sci 2023; 24:ijms24031891. [PMID: 36768211 PMCID: PMC9916039 DOI: 10.3390/ijms24031891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/21/2023] Open
Abstract
Schizophrenia (SZ) is a serious mental disorder that is typically treated with antipsychotic medication. Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile.
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Affiliation(s)
- Daniel Pérez-Rodríguez
- NeuroEpigenetics Lab, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain
| | - Maria Aránzazu Penedo
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain
- Grupo de Neurofarmacología de Las Adicciones y Los Trastornos Degenerativos (NEUROFAN), Universidad CEU San Pablo, 28925 Madrid, Spain
| | - Tania Rivera-Baltanás
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain
| | - Tonatiuh Peña-Centeno
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 Göttingen, Germany
| | - Susanne Burkhardt
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 Göttingen, Germany
| | - Andre Fischer
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 Göttingen, Germany
| | - José M. Prieto-González
- NeuroEpigenetics Lab, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Servicio de Neurología, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Grupo Trastornos del Movimiento, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - José Manuel Olivares
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain
- Department of Psychiatry, Área Sanitaria de Vigo, 36312 Vigo, Spain
| | - Hugo López-Fernández
- SING Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36213 Vigo, Spain
- CINBIO, Department of Computer Science, ESEI-Escuela Superior de Ingeniería Informática, Universidade de Vigo, 32004 Ourense, Spain
- Correspondence: (H.L.-F.); (R.C.A.-B.)
| | - Roberto Carlos Agís-Balboa
- NeuroEpigenetics Lab, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain
- Servicio de Neurología, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Grupo Trastornos del Movimiento, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
- Correspondence: (H.L.-F.); (R.C.A.-B.)
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Integrated Bioinformatics and Experimental Analysis Identified TRIM28 a Potential Prognostic Biomarker and Correlated with Immune Infiltrates in Liver Hepatocellular Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:6267851. [PMID: 36238495 PMCID: PMC9553339 DOI: 10.1155/2022/6267851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/10/2022] [Accepted: 09/02/2022] [Indexed: 11/18/2022]
Abstract
Background Since the 1970s, liver hepatocellular carcinoma (LIHC) has experienced a constant rise in incidence and mortality rates, making the identification of LIHC biomarkers very important. Tripartite Motif-Containing 28 (TRIM28) is a protein-coding gene which encodes the tripartite motif-containing proteins (TRIMs) family and is associated with specific chromatin regions. TRIM28 expression and its prognostic value and impact on the immune system in LIHC patients are being investigated for the first time. Methods The TRIM28 expression data from TCGA database was used to analyze TRIM28 expression, clinicopathological information, gene enrichment, and immune infiltration and conduct additional bioinformatics analysis. R language was used for statistical analysis. TIMER, CIBERSORT, and ssGSEA were used to assess immune responses of TRIM28 in LIHC. Next, the results were validated using GEPIA, ROC analysis, and immunohistochemical staining pictures from the THPA. GSE14520, GSE63898, and GSE87630 datasets were analyzed using ROC analysis to further evaluate TRIM28's diagnostic value. To ultimately determine TRIM28 expression, we performed qRT-PCR (quantitative real-time polymerase chain reaction). Results High TRIM28 expression level was associated with T classification, pathologic stage, histologic grade, and serum AFP levels. In patients with LIHC, TRIM28 was an independent risk factor for a poor prognosis. The pathways ligand-receptor interaction, which is critical in LIHC patients, were closely associated with TRIM28 expression, and the function of DC could be suppressed by overexpression of TRIM28. As a final step, our results were validated by GEO data and qRT-PCR. Conclusions TRIM28 will shed new light on LIHC mechanisms. As an effective diagnostic and intervention tool, this gene will be able to diagnose and treat LIHC at an early stage.
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Liu Y, Cao B, Hu L, Ye J, Tian W, He X. The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28. Front Cell Dev Biol 2022; 10:922675. [PMID: 35927984 PMCID: PMC9344466 DOI: 10.3389/fcell.2022.922675] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/17/2022] [Indexed: 01/10/2023] Open
Abstract
The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also independently ubiquitinates p53 as an E3 ligase activated by MAGE-C2. Moreover, MAGE-C2 is highly expressed in various cancers, but the detailed mechanisms of MAGE-C2 involved in MDM2/TRIM28-mediated p53 ubiquitination remain unknown. Here, we found that MAGE-C2 directly interacts with MDM2 through its conserved MHD domain to inhibit the activity of MDM2 on p53 ubiquitination. Furthermore, TRIM28 acts as an MAGE-C2 binding partner and directly competes with MAGE-C2 for MDM2 interaction, thus releasing the inhibitory role of MAGE-C2 and promoting p53 ubiquitination. MAGE-C2 suppresses cell proliferation in TRIM28-deficient cells, but the overexpression of TRIM28 antagonizes the inhibitory role of MAGE-C2 and accumulates p53 ubiquitination to promote cell proliferation. This study clarified the molecular link of MAGE-C2 in two major E3 systems MDM2 and TRIM28 on p53 ubiquitination. Our results revealed the molecular function of how MAGE-C2 and TRIM28 contribute to p53 ubiquitination and cell proliferation, in which MAGE-C2 acts as a potential inhibitor of MDM2 and TRIM28 is a vital regulator for MAGE-C2 function in p53 protein level and cell proliferation. This work would be helpful to understand the regulation mechanism of tumor suppressor p53.
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Wang R, Fu Y, Yao M, Cui X, Zhao Y, Lu X, Li Y, Lin Y, He S. The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin. FEBS J 2022; 289:6400-6419. [PMID: 35596723 DOI: 10.1111/febs.16531] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/21/2022] [Accepted: 05/19/2022] [Indexed: 11/26/2022]
Abstract
Hematological and neurological expressed 1 (HN1) is closely associated with the proliferation and metastasis of various tumors. However, the physiological functions and clinical significance of HN1 in hepatocellular carcinoma (HCC) remain indistinct. In this study, we investigated the role of HN1 in the pathogenesis of HCC and the underlying mechanism using clinical data from HCC patients, in vitro experiments utilizing HCC cell lines and in vivo animal models. We demonstrated that the overexpressed HN1 in HCC was correlated with patients' adverse outcomes. The gain and loss of function experiments indicated that HN1 could promote the proliferation, migration, and invasion of HCC cells in vitro. Furthermore, we found that HN1 knockdown sensitized HCC cells to oxaliplatin. Mechanically, HN1 prevented HMGB1 protein from ubiquitination and degradation via the autophagy-lysosome pathway, which was related to the interaction between HN1 protein and TRIM28 protein. In the nucleus, the downregulation of HMGB1 followed by HN1 knockdown resulted in increased DNA damage and cell death in the oxaliplatin-treated HCC cells. In the cytoplasm, HN1 regulated autophagy via HMGB1. Furthermore, HN1 knockdown in combination with HMGB1 overexpression restored the aggressive phenotypes of HCC cells and the sensitivity of these cells to oxaliplatin. HN1 knockdown inhibited the tumor growth and metastasis, and promoted the anticancer efficiency of oxaliplatin in vivo. In conclusion, our data suggest that the HN1/HMGB1 axis plays an important role in the development/progression and chemotherapy of HCC. Our findings indicate that the HN1/HMGB1 axis may be a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Ruhua Wang
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yunong Fu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Menglin Yao
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Xiaomeng Cui
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yan Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Xinlan Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yarui Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yiguang Lin
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Shuixiang He
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
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Li Y, Yang C, Wang H, Zhao L, Kong Q, Cang Y, Zhao S, Lv L, Li Y, Mao B, Ma P. Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression. J Mol Cell Biol 2022; 14:6510822. [PMID: 35040952 PMCID: PMC8982406 DOI: 10.1093/jmcb/mjab082] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/12/2021] [Accepted: 12/30/2021] [Indexed: 11/21/2022] Open
Abstract
Sonic hedgehog (Shh) signaling is essential for the proliferation of cerebellar granule neuron progenitors (CGNPs), and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma (MB). During vertebrate neural development, RNF220, a ubiquitin E3 ligase, is involved in spinal cord patterning by modulating the subcellular location of glioma-associated oncogene homologs (Glis) through ubiquitination. RNF220 is also required for full activation of Shh signaling during cerebellum development in an epigenetic manner through targeting embryonic ectoderm development. ZC4H2 was reported to be involved in spinal cord patterning by acting as an RNF220 stabilizer. Here, we provided evidence to show that ZC4H2 is also required for full activation of Shh signaling in CGNP and MB progression by stabilizing RNF220. In addition, we found that the ubiquitin E3 ligase RING finger LIM domain-binding protein (RLIM) is responsible for ZC4H2 stabilization via direct ubiquitination, through which RNF220 is also thus stabilized. RLIM is a direct target of Shh signaling and is also required for full activation of Shh signaling in CGNP and MB cell proliferation. We further provided clinical evidence to show that the RLIM‒ZC4H2‒RNF220 cascade is involved in Shh-group MB progression. Disease-causative human RLIM and ZC4H2 mutations affect their interaction and regulation. Therefore, our study sheds light on the regulation of Shh signaling during cerebellar development and MB progression and provides insights into neural disorders caused by RLIM or ZC4H2 mutations.
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Affiliation(s)
- Yuwei Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Chencheng Yang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Huishan Wang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Ling Zhao
- Experimental Animal Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Qinghua Kong
- Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650223, China
| | - Yu Cang
- Department of Urology, the Affiliated Hospital of Yunnan University, Kunming 650021, China
| | - Shuhua Zhao
- First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Longbao Lv
- Experimental Animal Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Yan Li
- Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650223, China
| | - Bingyu Mao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
| | - Pengcheng Ma
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
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Yuan P, Yan J, Wang S, Guo Y, Xi X, Han S, Yin J, Peng B, He X, Bodem J, Liu W. Trim28 acts as restriction factor of prototype foamy virus replication by modulating H3K9me3 marks and destabilizing the viral transactivator Tas. Retrovirology 2021; 18:38. [PMID: 34903241 PMCID: PMC8670036 DOI: 10.1186/s12977-021-00584-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/26/2021] [Indexed: 12/17/2022] Open
Abstract
Background Prototype foamy virus (PFV) is nonpathogenic complex retroviruses that express a transcriptional transactivator Tas, which is essential for the activity of viral long terminal repeat (LTR) promoter and internal promoter (IP). Tripartite motif-containing protein 28 (Trim28) is well known as a scaffold protein normally enriched in gene promoter region to repress transcription. We sought to determine if whether Trim28 could be enriched in PFV promoter region to participate the establishment of PFV latency infection. Results In this study, we show that Trim28 restricts Tas-dependent transactivation activity of PFV promoter and negatively regulates PFV replication. Trim28 was found to be enriched in LTR instead of IP promoter regions of PFV genome and contribute to the maintenance of histone H3K9me3 marks on the LTR promoter. Furthermore, Trim28 interacts with Tas and colocalizes with Tas in the nucleus. Besides, we found that Trim28, an E3 ubiquitin ligase, binds directly to and promotes Tas for ubiquitination and degradation. And the RBCC domain of Trim28 is required for the ubiquitination and degradation of Tas. Conclusions Collectively, our findings not only identify a host factor Trim28 negatively inhibits PFV replication by acting as transcriptional restriction factor enriched in viral LTR promoter through modulating H3K9me3 mark here, but also reveal that Trim28 mediated ubiquitin proteasome degradation of Tas as a mechanism underlying Trim28 restricts Tas-dependent transcription activity of PFV promoter and PFV replication. These findings provide new insights into the process of PFV latency establishment. Graphical Abstract ![]()
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Affiliation(s)
- Peipei Yuan
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.,Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Jun Yan
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Shuang Wang
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yang Guo
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Xueyan Xi
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Song Han
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jun Yin
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Biwen Peng
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiaohua He
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jochen Bodem
- Institut für Virologie und Immunbiologie, Julius-Maximilians-Universität Würzburg, 97078, Würzburg, Germany
| | - Wanhong Liu
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China. .,Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
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Zou C, Liao J, Hu D, Su Y, Lin H, Lin K, Luo X, Zheng X, Zhang L, Huang T, Lin X. SNHG8 Promotes the Progression of Epstein-Barr Virus-Associated Gastric Cancer via Sponging miR-512-5p and Targeting TRIM28. Front Oncol 2021; 11:734694. [PMID: 34722282 PMCID: PMC8554152 DOI: 10.3389/fonc.2021.734694] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/23/2021] [Indexed: 11/18/2022] Open
Abstract
SNHG8, a family member of small nucleolar RNA host genes (SNHG), has been reported to act as an oncogene in gastric carcinoma (GC). However, its biological function in Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) remains unclear. This study investigated the role of SNHG8 in EBVaGC. Sixty-one cases of EBVaGC, 20 cases of non-EBV-infected gastric cancer (EBVnGC), and relative cell lines were studied for the expression of SNHG8 and BHRF1 (BCL2 homolog reading frame 1) encoded by EBV with Western blot and qRT-PCR assays. The relationship between the expression levels of SNHG8 and the clinical outcome in 61 EBVaGC cases was analyzed. Effects of overexpression or knockdown of BHRF1, SNHG8, or TRIM28 on cell proliferation, migration, invasion, and cell cycle and the related molecules were determined by several assays, including cell proliferation, colony assay, wound healing assay, transwell invasion assay, cell circle with flow cytometry, qRT-PCR, and Western blot for expression levels. The interactions among SNHG8, miR-512-5p, and TRIM28 were determined with Luciferase reporter assay, RNA immunoprecipitation (RIP), pull-down assays, and Western blot assay. The in vivo activity of SNHG8 was assessed with SNHG8 knockdown tumor xenografts in zebrafish. Results demonstrated that the following. (1) BHRF1 and SNHG8 were overexpressed in EBV-encoded RNA 1-positive EBVaGC tissues and cell lines. BHRF1 upregulated the expressions of SNHG8 and TRIM28 in AGS. (2) SNHG8 overexpression had a significant correlation with tumor size and vascular tumor thrombus. Patients with high SNHG8 expression had poorer overall survival (OS) compared to those with low SNHG8 expression. (3) SNHG8 overexpression promoted EBVaGC cell proliferation, migration, and invasion in vitro and in vivo, cell cycle arrested at the G2/M phase via the activation of BCL-2, CCND1, PCNA, PARP1, CDH1, CDH2 VIM, and Snail. (4) Results of dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assays indicated that SNHG8 sponged miR-512-5p, which targeted on TRIM28 and promoted cancer malignant behaviors of EBVaGC cells. Our data suggest that BHRF1 triggered the expression of SNHG8, which sponged miR-512-5p and upregulated TRIM28 and a set of effectors (such as BCL-2, CCND1, CDH1, CDH2 Snail, and VIM) to promote EBVaGC tumorigenesis and invasion. SNHG8 could be an independent prognostic factor for EBVaGC and sever as target for EBVaGC therapy.
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Affiliation(s)
- Changyan Zou
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Jinrong Liao
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Dan Hu
- Department of Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Ying Su
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Huamei Lin
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Keyu Lin
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Xingguan Luo
- Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
| | - Xiongwei Zheng
- Department of Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Lurong Zhang
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Tao Huang
- Bio-Med Big Data Center, Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Xiandong Lin
- Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China.,Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, China
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Intranasal Administration of Codium fragile Polysaccharide Elicits Anti-Cancer Immunity against Lewis Lung Carcinoma. Int J Mol Sci 2021; 22:ijms221910608. [PMID: 34638944 PMCID: PMC8508762 DOI: 10.3390/ijms221910608] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 01/02/2023] Open
Abstract
Natural polysaccharides have shown promising effects on the regulation of immunity in animals. In this study, we examined the immune stimulatory effect of intranasally administered Codium fragile polysaccharides (CFPs) in mice. Intranasal administration of CFPs in C57BL/6 mice induced the upregulation of surface activation marker expression in macrophages and dendritic cells (DCs) in the mediastinal lymph node (mLN) and the production of interleukin-6 (IL-6), IL-12p70, and tumor necrosis factor-α in bronchoalveolar lavage fluid. Moreover, the number of conventional DCs (cDCs) was increased in the mLNs by the upregulation of C-C motif chemokine receptor 7 expression, and subsets of cDCs were also activated following the intranasal administration of CFP. In addition, the intranasal administration of CFPs promoted the activation of natural killer (NK) and T cells in the mLNs, which produce pro-inflammatory cytokines and cytotoxic mediators. Finally, daily administration of CFPs inhibited the infiltration of Lewis lung carcinoma cells into the lungs, and the preventive effect of CFPs on tumor growth required NK and CD8 T cells. Furthermore, CFPs combined with anti-programmed cell death-ligand 1 (PD-L1) antibody (Ab) improved the therapeutic effect of anti-PD-L1 Ab against lung cancer. Therefore, these data demonstrated that the intranasal administration of CFP induced mucosal immunity against lung cancer.
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Márquez-Cantudo L, Ramos A, Coderch C, de Pascual-Teresa B. Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation. Molecules 2021; 26:molecules26185606. [PMID: 34577077 PMCID: PMC8467390 DOI: 10.3390/molecules26185606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/21/2022] Open
Abstract
Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.
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Jin JO, Puranik N, Bui QT, Yadav D, Lee PCW. The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer. Int J Mol Sci 2021; 22:9629. [PMID: 34502538 PMCID: PMC8431782 DOI: 10.3390/ijms22179629] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/03/2021] [Accepted: 09/03/2021] [Indexed: 12/25/2022] Open
Abstract
The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.
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Affiliation(s)
- Jun-O Jin
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Nidhi Puranik
- Biological Sciences Department, Bharathiar University, Coimbatore 641046, Tamil Nadu, India;
| | - Quyen Thu Bui
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
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Boyson SP, Gao C, Quinn K, Boyd J, Paculova H, Frietze S, Glass KC. Functional Roles of Bromodomain Proteins in Cancer. Cancers (Basel) 2021; 13:3606. [PMID: 34298819 PMCID: PMC8303718 DOI: 10.3390/cancers13143606] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/09/2021] [Accepted: 07/09/2021] [Indexed: 12/31/2022] Open
Abstract
Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.
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Affiliation(s)
- Samuel P. Boyson
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA;
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA;
| | - Cong Gao
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; (C.G.); (J.B.); (H.P.)
| | - Kathleen Quinn
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA;
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; (C.G.); (J.B.); (H.P.)
| | - Joseph Boyd
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; (C.G.); (J.B.); (H.P.)
| | - Hana Paculova
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; (C.G.); (J.B.); (H.P.)
| | - Seth Frietze
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; (C.G.); (J.B.); (H.P.)
- University of Vermont Cancer Center, Burlington, VT 05405, USA
| | - Karen C. Glass
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA;
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA;
- University of Vermont Cancer Center, Burlington, VT 05405, USA
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Zhou Z, Qiu R, Liu W, Yang T, Li G, Huang W, Teng X, Yang Y, Yu H, Yang Y, Wang Y. BCAS3 exhibits oncogenic properties by promoting CRL4A-mediated ubiquitination of p53 in breast cancer. Cell Prolif 2021; 54:e13088. [PMID: 34240781 PMCID: PMC8349660 DOI: 10.1111/cpr.13088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/10/2021] [Accepted: 06/13/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives Breast cancer‐amplified sequence 3 (BCAS3) was initially found to be amplified in human breast cancer (BRCA); however, there has been little consensus on the functions of BCAS3 in breast tumours. Materials and methods We analysed BCAS3 expression in BRCA using bio‐information tools. Affinity purification and mass spectrometry were employed to identify BCAS3‐associated proteins. GST pull‐down and ubiquitination assays were performed to analyse the interaction mechanism between BCAS3/p53 and CUL4A‐RING E3 ubiquitin ligase (CRL4A) complex. BCAS3 was knocked down individually or in combination with p53 in MCF‐7 cells to further explore the biological functions of the BCAS3/p53 axis. The clinical values of BCAS3 for BRCA progression were evaluated via semiquantitative immunohistochemistry (IHC) analysis and Cox regression. Results We reported that the expression level of BCAS3 in BRCA was higher than that in adjacent normal tissues. High BCAS3 expression promoted growth, inhibited apoptosis and conferred chemoresistance in breast cancer cells. Mechanistically, BCAS3 overexpression fostered BRCA cell growth by interacting with the CRL4A complex and promoting ubiquitination and proteasomal degradation of p53. Furthermore, BCAS3 could regulate cell growth, apoptosis and chemoresistance through a p53‐mediated mechanism. Clinically, BCAS3 overexpression was significantly correlated with a malignant phenotype. Moreover, higher expression of BCAS3 correlates with shorter overall survival (OS) in BRCA. Conclusions The functional characterization of BCAS3 offers new insights into the oncogenic properties and chemotherapy resistance in breast cancer.
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Affiliation(s)
- Zhe Zhou
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Rongfang Qiu
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui, China
| | - Wei Liu
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Tianshu Yang
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Gen Li
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Wei Huang
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xu Teng
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yunkai Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hefen Yu
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yang Yang
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui, China
| | - Yan Wang
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Beijing Key Laboratory for Tumor Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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