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Zhang B, Matsumoto Y. Integrated Network Analysis Decipher ZNF384-Related miR-20b-5p and miR-424-5p in Colon Adenocarcinoma. Cancer Rep (Hoboken) 2025; 8:e70233. [PMID: 40405535 PMCID: PMC12098962 DOI: 10.1002/cnr2.70233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 04/09/2025] [Accepted: 05/09/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND ZNF384 is a C2H2-type zinc finger protein (ZNF) which is implicated in DNA double-strand break (DSB) repair through the classical non-homologous end-joining (cNHEJ) pathway. AIMS To clarify the regulatory mechanisms involving ZNF384 in colon adenocarcinoma (COAD). METHODS AND RESULTS First, we conducted a differential expression gene (DEG) analysis of mRNA and lncRNA using TCGA-COAD RNA-Seq data. We also identified ZNF384-related mRNAs through Pearson's correlation coefficient calculation and conducted weighted gene co-expression network analysis (WGCNA) for these genes, leading to the identification of a cluster of 331 genes with strongly positive correlation to tumor, 84 of which overlapped with DEGs. Gene functional analysis showed enrichment of genes in DNA repair, replication fork, and cell cycle checkpoint signaling pathways. Protein-protein interaction (PPI) network analysis of these 84 genes led to the identification of the top 20 key mRNAs. Then we employed three machine learning methods to refine our selection of candidate genes from these intersecting mRNAs. We constructed a competitive endogenous RNA (ceRNA) network and identified two significant intersecting miRNAs, miR-20b-5p and miR-424-5p, which have been shown to act as a tumor suppressor gene and an oncogene, respectively. Additionally, we found that KIF14 and KIF18B are regulated by these two miRNAs in this ceRNA network, particularly in DNA damage repair and cell cycle. Finally, validation using an external dataset from the GEO database confirmed their expression patterns. CONCLUSION The current study clarifies the mechanisms of how miR-20b-5p and miR-424-5p work in colon cancer and underscores their predictive capabilities in colon cancer.
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Affiliation(s)
- Bo Zhang
- Department of Transdisciplinary Science and EngineeringSchool of Environment and Society, Institute of Science TokyoTokyoJapan
- Laboratory for Zero‐Carbon Energy, Institute of Integrated ResearchInstitute of Science TokyoTokyoJapan
| | - Yoshihisa Matsumoto
- Department of Transdisciplinary Science and EngineeringSchool of Environment and Society, Institute of Science TokyoTokyoJapan
- Laboratory for Zero‐Carbon Energy, Institute of Integrated ResearchInstitute of Science TokyoTokyoJapan
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2
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Zhang Y, Lu Y, Wang N, Hao F, Chen Y, Fei X, Wang J. Ascending E2F7a/b ratio facilitates KLF13 transcription in hepatocellular carcinoma and correlates with the abundance of binuclear hepatocytes (ABH) modulation for short-term recurrence. FASEB J 2025; 39:e70485. [PMID: 40116212 PMCID: PMC11926945 DOI: 10.1096/fj.202402520r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 02/25/2025] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
Short-term recurrence after surgery severely threatens patients' lives and leads to dismal outcomes in hepatocellular carcinoma (HCC). Our previous research proposed the abundance of binuclear hepatocytes (ABH) as an independent indicator related to the cytokinesis regulator Anillin and significantly associated with HCC recurrence. The exact mechanism of ABH modulation has not been clearly illustrated. In this study, we intensively investigated the probable regulation mechanism and noticed a contradiction between E2F7 upregulation and ABH attenuation. As we discovered, E2F7 has two isoforms, E2F7a and E2F7b, and we innovatively define a value of the E2F7a/b ratio using a cutoff value of 6.5. E2F7 upregulation in the paracancerous tissues was predominantly presented by the E2F7a isoform, leading to an increase in the E2F7a/b ratio, instead of E2F7b as a main component in non-cancerous tissues, and is associated with short-term recurrence. We further found that KLF13 transcriptionally promotes Anillin expression in HCC and was suppressively impacted by E2F7b, but not by the highly expressed E2F7a. Hence, the ascending E2F7a/b ratio induced significant upregulation of KLF13 and participated in the attenuation of ABH in the paracancerous liver tissues. In conclusion, E2F7 presents a particular expression status in HCC by predominantly upregulating E2F7a rather than E2F7b. The ascending E2F7a/b ratio weakens the suppressive effect on KLF13 transcription and sequentially participates in ABH attenuation, associated with short-term HCC recurrence post-operation.
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Affiliation(s)
- Yian Zhang
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Yiquan Lu
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Nan Wang
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Fengjie Hao
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Yongjun Chen
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Xiaochun Fei
- Department of Pathology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Junqing Wang
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
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3
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Jia MY, Wu C, Fu Z, Xu WB, Liu J, Wu CY, Zeng XY, Wu YL, Yan H. Targeting the HuR/E2F7 axis synergizes with bortezomib against multiple myeloma. Acta Pharmacol Sin 2025:10.1038/s41401-025-01529-3. [PMID: 40133626 DOI: 10.1038/s41401-025-01529-3] [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: 11/10/2024] [Accepted: 02/28/2025] [Indexed: 03/27/2025]
Abstract
Multiple myeloma (MM) is a malignant hematological disease caused by the proliferation of abnormal plasma cells in the bone marrow and is still incurable. Relapse and drug resistance are common in MM. New therapeutic targets are urgently needed for MM treatment. Human antigen R (HuR) has been reported to play an important role in the malignant biological behavior of a variety of tumors, but its role in MM remains unclear. In this study, we found that HuR was highly expressed in MM patients and associated with a poor prognosis by analyzing public datasets. We found that targeting HuR with short hairpin RNA (shRNA) or its inhibitor CMLD-2 had significant anti-MM effects both in vitro and in vivo. The overexpression of HuR promotes MM cell proliferation in vitro and in vivo. Moreover, we demonstrated that bortezomib drug sensitivity increased and decreased with the knockdown and overexpression of HuR, respectively. This result provides a rationale for our subsequent combination of CMLD-2 with bortezomib in the treatment of MM. To further explore the mechanism of HuR in MM, we performed RNA sequencing and identified its downstream molecule, E2F7. HuR upregulated E2F7 expression by increasing the stability of its mRNA in MM cells. Higher levels of E2F7 were associated with a poorer prognosis. E2F7 knockdown had anti-MM effects in vitro and in vivo. E2F7 overexpression partially rescued the cell proliferation inhibition and apoptosis caused by targeting HuR in MM cells. We subsequently demonstrated that CMLD-2 synergized with the anti-MM effect of bortezomib both in vitro and in vivo. In conclusion, targeting the HuR/E2F7 axis synergizes with bortezomib against MM. Therefore, the HuR/E2F7 axis may serve as a promising therapeutic target for MM.
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Affiliation(s)
- Ming-Yuan Jia
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Wu
- Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ze Fu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wen-Bin Xu
- Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jia Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Cheng-Yu Wu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xin-Yi Zeng
- Department of Hematology, Huadong Hospital Affiliated with Fudan University, Shanghai, 200040, China
| | - Ying-Li Wu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
| | - Hua Yan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Ferrando-Marco M, Barkoulas M. EFL-3/E2F7 modulates Wnt signalling by repressing the Nemo-like kinase LIT-1 during asymmetric epidermal cell division in Caenorhabditis elegans. Development 2025; 152:DEV204546. [PMID: 40026193 PMCID: PMC11925398 DOI: 10.1242/dev.204546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/02/2025] [Indexed: 03/04/2025]
Abstract
The E2F family of transcription factors is conserved in higher eukaryotes and plays pivotal roles in controlling gene expression during the cell cycle. Most canonical E2Fs associate with members of the Dimerisation Partner (DP) family to activate or repress target genes. However, atypical repressors, such as E2F7 and E2F8, lack DP interaction domains and their functions are less understood. We report here that EFL-3, the E2F7 homologue of Caenorhabditis elegans, regulates epidermal stem cell differentiation. We show that phenotypic defects in efl-3 mutants depend on the Nemo-like kinase LIT-1. EFL-3 represses lit-1 expression through direct binding to a lit-1 intronic element. Increased LIT-1 expression in efl-3 mutants reduces POP-1/TCF nuclear distribution, and consequently alters Wnt pathway activation. Our findings provide a mechanistic link between an atypical E2F family member and NLK during C. elegans asymmetric cell division, which may be conserved in other animals.
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Wei J, Gao C, Lu C, Wang L, Dong D, Sun M. The E2F family: a ray of dawn in cardiomyopathy. Mol Cell Biochem 2025; 480:825-839. [PMID: 38985251 DOI: 10.1007/s11010-024-05063-4] [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: 03/21/2024] [Accepted: 06/29/2024] [Indexed: 07/11/2024]
Abstract
Cardiomyopathies are a group of heterogeneous diseases, characterized by abnormal structure and function of the myocardium. For many years, it has been a hot topic because of its high morbidity and mortality as well as its complicated pathogenesis. The E2Fs, a group of transcription factors found extensively in eukaryotes, play a crucial role in governing cell proliferation, differentiation, and apoptosis, meanwhile their deregulated activity can also cause a variety of diseases. Based on accumulating evidence, E2Fs play important roles in cardiomyopathies. In this review, we describe the structural and functional characteristics of the E2F family and its role in cardiomyocyte processes, with a focus on how E2Fs are associated with the onset and development of cardiomyopathies. Moreover, we discuss the great potential of E2Fs as biomarkers and therapeutic targets, aiming to provide a reference for future research.
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Affiliation(s)
- Jinwen Wei
- College of Exercise and Health, Shenyang Sport University, No.36 Jinqiansong East Road, Shenyang, 110102, Liaoning, People's Republic of China
| | - Can Gao
- College of Exercise and Health, Shenyang Sport University, No.36 Jinqiansong East Road, Shenyang, 110102, Liaoning, People's Republic of China
| | - Changxu Lu
- College of Exercise and Health, Shenyang Sport University, No.36 Jinqiansong East Road, Shenyang, 110102, Liaoning, People's Republic of China
| | - Lijie Wang
- Department of Cardiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110033, Liaoning, People's Republic of China
| | - Dan Dong
- College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Mingli Sun
- College of Exercise and Health, Shenyang Sport University, No.36 Jinqiansong East Road, Shenyang, 110102, Liaoning, People's Republic of China.
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Wu T, Jiang F, Wu F, Zheng G, Li Y, Wu L. E2F1 and E2F7 regulate gastric cancer cell proliferation, respectively, through transcriptional activation and transcriptional repression of MYBL2. J Biol Chem 2025; 301:108027. [PMID: 39613162 PMCID: PMC11731210 DOI: 10.1016/j.jbc.2024.108027] [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: 05/30/2024] [Revised: 10/22/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024] Open
Abstract
Gastric cancer (GC) is the most common malignant tumor of the digestive tract. However, the molecular pathogenesis is not well understood. Through bioinformatic analysis and analyzing clinical tissue samples, we found that E2F1 and E2F7 as well as their potential downstream target MYBL2 were all upregulated in GC tissues and that their expressions correlated with patient prognosis. While knockdown of E2F1 or MYBL2 inhibited cell proliferation and promoted apoptosis, knockdown of E2F7 promoted cell proliferation but had no effects on apoptosis. Chromatin immunoprecipitation and dual luciferase reporter assays demonstrated that MYBL2 was transcriptionally activated and repressed by E2F1 and E2F7, respectively. Importantly, in vitro and ex vivo experiments demonstrated that the effects of E2F1 and E2F7 on GC cell proliferation were significantly attenuated by reversely modulating MYBL2 expression, indicating that MYBL2 is a direct and functionally relevant target of E2F1 and E2F7 in GC cells. Furthermore, the effects of E2F1 and E2F7 on GC cell proliferation through transcriptional regulation of MYBL2 can be mediated by the PI3K/AKT signaling pathway. Interestingly, we found differential nucleocytoplasmic distribution of E2F7 in GC cells with functional relevance. Taken together, our data suggest that targeted therapies of GC may be achieved from three different angles, E2F1, E2F7, and MYBL2 themselves, E2F1/E2F7 expression balance, and E2F7 nuclear localization.
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Affiliation(s)
- Tianyi Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Fengli Jiang
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China; Department of Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fan Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Guoliang Zheng
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China; Department of Gastric Surgery, Cancer Hospital of China Medical University (Liaoning Cancer Hospital and Institute), Shenyang, China
| | - Yang Li
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China; Department of Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lizhao Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China.
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7
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Schaal DL, Amucheazi AA, Jones SC, Nkadi EH, Scott RS. Epstein-Barr virus replication within differentiated epithelia requires pRb sequestration of activator E2F transcription factors. J Virol 2024; 98:e0099524. [PMID: 39291960 PMCID: PMC11494884 DOI: 10.1128/jvi.00995-24] [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: 06/06/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Epstein-Barr virus (EBV) co-infections with human papillomavirus (HPV) have been observed in oropharyngeal squamous cell carcinoma. Modeling EBV/HPV co-infection in organotypic epithelial raft cultures revealed that HPV16 E7 inhibited EBV productive replication through the facilitated degradation of the retinoblastoma protein pRb/p105. To further understand how pRb is required for EBV productive replication, we generated CRISPR-Cas9 pRb knockout (KO) normal oral keratinocytes (NOKs) in the context of wild-type and mutant K120E p53. EBV replication was examined in organotypic rafts as a physiological correlate for epithelial differentiation. In pRb KO rafts, EBV DNA copy number was statistically decreased compared to vector controls, regardless of p53 context. Loss of pRb did not affect EBV binding or internalization of calcium-treated NOKs or early infection of rafts. Rather, the block in EBV replication correlated with impaired immediate early gene expression. An EBV infection time course in rafts with mutant p53 demonstrated that pRb-positive basal cells were initially infected with delayed replication occurring in differentiated layers. Loss of pRb showed increased S-phase progression makers and elevated activator E2F activity in raft tissues. Complementation with a panel of pRb/E2F binding mutants showed that wild type or pRb∆685 mutant capable of E2F binding reduced S-phase marker gene expression, rescued EBV DNA replication, and restored BZLF1 expression in pRb KO rafts. However, pRb KO complemented with pRb661W mutant, unable to bind E2Fs, failed to rescue EBV replication in raft culture. These findings suggest that EBV productive replication in differentiated epithelium requires pRb inhibition of activator E2Fs to restrict S-phase progression.IMPORTANCEA subset of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma is co-positive for Epstein-Barr virus (EBV). Potential oncogenic viral interactions revealed that HPV16 E7 inhibited productive EBV replication within the differentiated epithelium. As E7 mediates the degradation of pRb, we aimed to establish how pRb is involved in EBV replication. In the context of differentiated epithelium using organotypic raft culture, we evaluated how the loss of pRb affects EBV lytic replication to better comprehend EBV contributions to carcinogenesis. In this study, ablation of pRb interfered with EBV replication at the level of immediate early gene expression. Loss of pRb increased activator E2Fs and associated S-phase gene expression throughout the differentiated epithelium. Complementation studies showed that wild type and pRb mutant capable of binding to E2F rescued EBV replication, while pRb mutant lacking E2F binding did not. Altogether, these studies support that in differentiated tissues, HPV16 E7-mediated degradation of pRb inhibits EBV replication through unregulated E2F activity.
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Affiliation(s)
- Danielle L. Schaal
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Akajiugo A. Amucheazi
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Sarah C. Jones
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Ebubechukwu H. Nkadi
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Rona S. Scott
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
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8
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Sun M, Ji Y, Zhang G, Li Y, Dong F, Wu T. Posttranslational modifications of E2F family members in the physiological state and in cancer: Roles, mechanisms and therapeutic targets. Biomed Pharmacother 2024; 178:117147. [PMID: 39053422 DOI: 10.1016/j.biopha.2024.117147] [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: 05/09/2024] [Revised: 07/01/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024] Open
Abstract
The E2F transcription factor family, whose members are encoded by the E2F1-E2F8 genes, plays pivotal roles in the cell cycle, apoptosis, metabolism, stemness, metastasis, aging, angiogenesis, tumor promotion or suppression, and other biological processes. The activity of E2Fs is regulated at multiple levels, with posttranslational modifications being an important regulatory mechanism. There are numerous types of posttranslational modifications, among which phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, and poly(ADP-ribosyl)ation are the most commonly studied in the context of the E2F family. Posttranslational modifications of E2F family proteins regulate their biological activity, stability, localization, and interactions with other biomolecules, affecting cell proliferation, apoptosis, DNA damage, etc., and thereby playing roles in physiological and pathological processes. Notably, these modifications do not always act alone but rather form an interactive regulatory network. Currently, several drugs targeting posttranslational modifications are being studied or clinically applied, in which the proteolysis-targeting chimera and molecular glue can target E2Fs. This review aims to summarize the roles and regulatory mechanisms of different PTMs of E2F family members in the physiological state and in cancer and to briefly discuss their clinical significance and potential therapeutic use.
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Affiliation(s)
- Mingyang Sun
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, China
| | - Yitong Ji
- Department of Clinical Medicine, China Medical University, Shenyang 110122, China
| | - Guojun Zhang
- Department of Physiology, College of Basic Medical Sciences, Shenyang Medical College, Shenyang 110034, China
| | - Yang Li
- Department of Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Fengming Dong
- Department of Urology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Tianyi Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, China.
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Aptullahoglu E, Nakjang S, Wallis JP, Marr H, Marshall S, Willmore E, Lunec J. RNA Sequencing Reveals Candidate Genes and Pathways Associated with Resistance to MDM2 Antagonist Idasanutlin in TP53 Wild-Type Chronic Lymphocytic Leukemia. Biomedicines 2024; 12:1388. [PMID: 39061962 PMCID: PMC11274024 DOI: 10.3390/biomedicines12071388] [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: 05/20/2024] [Revised: 06/17/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a genetically and clinically diverse hematological cancer affecting middle-aged and elderly individuals. Novel targeted therapy options are needed for patients who relapse following initial responses or who are intrinsically resistant to current treatments. There is a growing body of investigation currently underway on MDM2 inhibitors in clinical trials, reflecting the increasing interest in including these drugs in cancer treatment regimens. One of the developed compounds, idasanutlin (RG7388), has shown promise in early-stage clinical trials. It is a second-generation MDM2-p53-binding antagonist with enhanced potency, selectivity, and bioavailability. In addition to the TP53 status, which is an important determinant of the response, we have shown in our previous studies that the SF3B1 mutational status is also an independent predictive biomarker of the ex vivo CLL patient sample treatment response to RG7388. The objective of this study was to identify novel biomarkers associated with resistance to RG7388. Gene set enrichment analysis of differentially expressed genes (DEGs) between RG7388-sensitive and -resistant CLL samples showed that the increased p53 activity led to upregulation of pro-apoptosis pathway genes while DNA damage response pathway genes were additionally upregulated in resistant samples. Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.
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Affiliation(s)
- Erhan Aptullahoglu
- Biosciences Instittute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Şeyh Edebali University, 11100 Bilecik, Türkiye
| | - Sirintra Nakjang
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast BT7 1NN, UK;
| | - Jonathan P. Wallis
- Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK; (J.P.W.); (H.M.)
| | - Helen Marr
- Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK; (J.P.W.); (H.M.)
| | - Scott Marshall
- Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland SR4 7TP, UK;
| | - Elaine Willmore
- Biosciences Instittute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - John Lunec
- Biosciences Instittute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
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Zhou Y, Nakajima R, Shirasawa M, Fikriyanti M, Zhao L, Iwanaga R, Bradford AP, Kurayoshi K, Araki K, Ohtani K. Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression. BIOLOGY 2023; 12:1511. [PMID: 38132337 PMCID: PMC10740672 DOI: 10.3390/biology12121511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.
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Affiliation(s)
- Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mariana Fikriyanti
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Andrew P. Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama, Fukushima 963-8611, Japan;
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
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11
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Wu Z, Su J, Li FL, Chen T, Mayner J, Engler A, Ma S, Li Q, Guan KL. YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis. Nat Commun 2023; 14:5916. [PMID: 37739954 PMCID: PMC10516997 DOI: 10.1038/s41467-023-41585-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/07/2023] [Indexed: 09/24/2023] Open
Abstract
Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.
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Affiliation(s)
- Zhengming Wu
- Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Junhui Su
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Fu-Long Li
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Jaimie Mayner
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Adam Engler
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Shenghong Ma
- Wellcome Sanger Institute, Cambridge, CB10 1RQ, UK
| | - Qingquan Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
| | - Kun-Liang Guan
- Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
- School of Life Sciences, Westlake University, Hangzhou, 310030, China.
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12
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Lin KH, Lee SC, Dacheux MA, Norman DD, Balogh A, Bavaria M, Lee H, Tigyi G. E2F7 drives autotaxin/Enpp2 transcription via chromosome looping: Repression by p53 in murine but not in human carcinomas. FASEB J 2023; 37:e23058. [PMID: 37358838 PMCID: PMC10364077 DOI: 10.1096/fj.202300838r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/31/2023] [Accepted: 06/13/2023] [Indexed: 06/27/2023]
Abstract
Dysregulation of the autotaxin (ATX, Enpp2)-lysophosphatidic acid (LPA) signaling in cancerous cells contributes to tumorigenesis and therapy resistance. We previously found that ATX activity was elevated in p53-KO mice compared to wild-type (WT) mice. Here, we report that ATX expression was upregulated in mouse embryonic fibroblasts from p53-KO and p53R172H mutant mice. ATX promoter analysis combined with yeast one-hybrid testing revealed that WT p53 directly inhibits ATX expression via E2F7. Knockdown of E2F7 reduced ATX expression and chromosome immunoprecipitation showed that E2F7 promotes Enpp2 transcription through cooperative binding to two E2F7 sites (promoter region -1393 bp and second intron 996 bp). Using chromosome conformation capture, we found that chromosome looping brings together the two E2F7 binding sites. We discovered a p53 binding site in the first intron of murine Enpp2, but not in human ENPP2. Binding of p53 disrupted the E2F7-mediated chromosomal looping and repressed Enpp2 transcription in murine cells. In contrast, we found no disruption of E2F7-mediated ENPP2 transcription via direct p53 binding in human carcinoma cells. In summary, E2F7 is a common transcription factor that upregulates ATX in human and mouse cells but is subject to steric interference by direct intronic p53 binding only in mice.
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Affiliation(s)
- Kuan-Hung Lin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Andrea Balogh
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Mitul Bavaria
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Hsinyu Lee
- Department of Life Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Gabor Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
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13
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Lee DY, Chun JN, Cho M, So I, Jeon JH. Emerging role of E2F8 in human cancer. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166745. [PMID: 37164180 DOI: 10.1016/j.bbadis.2023.166745] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/12/2023]
Abstract
E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.
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Affiliation(s)
- Da Young Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Nyeo Chun
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Minsoo Cho
- Independent researcher, Seoul, Republic of Korea
| | - Insuk So
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea.
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14
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Role of E2F transcription factor in Oral cancer: Recent Insight and Advancements. Semin Cancer Biol 2023; 92:28-41. [PMID: 36924812 DOI: 10.1016/j.semcancer.2023.03.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/27/2023] [Accepted: 03/06/2023] [Indexed: 03/16/2023]
Abstract
The family of mammalian E2F transcription factors (E2Fs) comprise of 8 members (E2F1-E2F8) classified as activators (E2F1-E2F3) and repressors (E2F4-E2F8) primarily regulating the expression of several genes related to cell proliferation, apoptosis and differentiation, mainly in a cell cycle-dependent manner. E2F activity is frequently controlled via the retinoblastoma protein (pRb), cyclins, p53 and the ubiquitin-proteasome pathway. Additionally, genetic or epigenetic changes result in the deregulation of E2F family genes expression altering S phase entry and apoptosis, an important hallmark for the onset and development of cancer. Although studies reveal E2Fs to be involved in several human malignancies, the mechanisms underlying the role of E2Fs in oral cancer lies nascent and needs further investigations. This review focuses on the role of E2Fs in oral cancer and the etiological factors regulating E2Fs activity, which in turn transcriptionally control the expression of their target genes, thus contributing to cell proliferation, metastasis, and drug/therapy resistance. Further, we will discuss therapeutic strategies for E2Fs, which may prevent oral tumor growth, metastasis, and drug resistance.
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15
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Gugnoni M, Lorenzini E, Faria do Valle I, Remondini D, Castellani G, Torricelli F, Sauta E, Donati B, Ragazzi M, Ghini F, Piana S, Ciarrocchi A, Manzotti G. Adding pieces to the puzzle of differentiated-to-anaplastic thyroid cancer evolution: the oncogene E2F7. Cell Death Dis 2023; 14:99. [PMID: 36765037 PMCID: PMC9918458 DOI: 10.1038/s41419-023-05603-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 02/12/2023]
Abstract
Anaplastic Thyroid Cancer (ATC) is the most aggressive and de-differentiated subtype of thyroid cancer. Many studies hypothesized that ATC derives from Differentiated Thyroid Carcinoma (DTC) through a de-differentiation process triggered by specific molecular events still largely unknown. E2F7 is an atypical member of the E2F family. Known as cell cycle inhibitor and keeper of genomic stability, in specific contexts its function is oncogenic, guiding cancer progression. We performed a meta-analysis on 279 gene expression profiles, from 8 Gene Expression Omnibus patient samples datasets, to explore the causal relationship between DTC and ATC. We defined 3 specific gene signatures describing the evolution from normal thyroid tissue to DTC and ATC and validated them in a cohort of human surgically resected ATCs collected in our Institution. We identified E2F7 as a key player in the DTC-ATC transition and showed in vitro that its down-regulation reduced ATC cells' aggressiveness features. RNA-seq and ChIP-seq profiling allowed the identification of the E2F7 specific gene program, which is mainly related to cell cycle progression and DNA repair ability. Overall, this study identified a signature describing DTC de-differentiation toward ATC subtype and unveiled an E2F7-dependent transcriptional program supporting this process.
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Affiliation(s)
- Mila Gugnoni
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Eugenia Lorenzini
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | | | - Daniel Remondini
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
| | - Gastone Castellani
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elisabetta Sauta
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy
| | - Benedetta Donati
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Moira Ragazzi
- Pathology Unit, Department of Oncology and Advanced Technologies, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Francesco Ghini
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Simonetta Piana
- Pathology Unit, Department of Oncology and Advanced Technologies, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy.
| | - Gloria Manzotti
- Laboratory of Translational Research, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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16
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Martino NA, Picardi E, Ciani E, D’Erchia AM, Bogliolo L, Ariu F, Mastrorocco A, Temerario L, Mansi L, Palumbo V, Pesole G, Dell’Aquila ME. Cumulus Cell Transcriptome after Cumulus-Oocyte Complex Exposure to Nanomolar Cadmium in an In Vitro Animal Model of Prepubertal and Adult Age. BIOLOGY 2023; 12:biology12020249. [PMID: 36829526 PMCID: PMC9953098 DOI: 10.3390/biology12020249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/25/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023]
Abstract
Cadmium (Cd), a highly toxic pollutant, impairs oocyte fertilization, through oxidative damage on cumulus cells (CCs). This study analysed the transcriptomic profile of CCs of cumulus-oocyte complexes (COCs) from adult and prepubertal sheep, exposed to Cd nanomolar concentration during in vitro maturation. In both age-groups, CCs of matured oocytes underwent RNA-seq, data analysis and validation. Differentially expressed genes (DEGs) were identified in adult (n = 99 DEGs) and prepubertal (n = 18 DEGs) CCs upon Cd exposure. Transcriptomes of adult CCs clustered separately between Cd-exposed and control samples, whereas prepubertal ones did not as observed by Principal Component Analysis. The transcriptomic signature of Cd-induced CC toxicity was identified by gene annotation and literature search. Genes associated with previous studies on ovarian functions and/or Cd effects were confirmed and new genes were identified, thus implementing the knowledge on their involvement in such processes. Enrichment and validation analysis showed that, in adult CCs, Cd acted as endocrine disruptor on DEGs involved in hormone biosynthesis, cumulus expansion, regulation of cell signalling, growth and differentiation and oocyte maturation, whereas in prepubertal CCs, Cd affected DEGs involved in CC development and viability and CC-oocyte communications. In conclusion, these DEGs could be used as valuable non-invasive biomarkers for oocyte competence.
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Affiliation(s)
- Nicola Antonio Martino
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
- Correspondence: ; Tel.: +39-0805443888
| | - Ernesto Picardi
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Elena Ciani
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Anna Maria D’Erchia
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Luisa Bogliolo
- Department of Veterinary Medicine, University of Sassari, Via Vienna n. 2, 07100 Sassari, Italy
| | - Federica Ariu
- Department of Veterinary Medicine, University of Sassari, Via Vienna n. 2, 07100 Sassari, Italy
| | - Antonella Mastrorocco
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Letizia Temerario
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Luigi Mansi
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Valeria Palumbo
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Graziano Pesole
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
| | - Maria Elena Dell’Aquila
- Department of Biosciences, Biotechnologies & Environment, University of Bari Aldo Moro, Via Edoardo Orabona, 70125 Bari, Italy
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17
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Deregulated E2F Activity as a Cancer-Cell Specific Therapeutic Tool. Genes (Basel) 2023; 14:genes14020393. [PMID: 36833320 PMCID: PMC9956157 DOI: 10.3390/genes14020393] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
The transcription factor E2F, the principal target of the tumor suppressor pRB, plays crucial roles in cell proliferation and tumor suppression. In almost all cancers, pRB function is disabled, and E2F activity is enhanced. To specifically target cancer cells, trials have been undertaken to suppress enhanced E2F activity to restrain cell proliferation or selectively kill cancer cells, utilizing enhanced E2F activity. However, these approaches may also impact normal growing cells, since growth stimulation also inactivates pRB and enhances E2F activity. E2F activated upon the loss of pRB control (deregulated E2F) activates tumor suppressor genes, which are not activated by E2F induced by growth stimulation, inducing cellular senescence or apoptosis to protect cells from tumorigenesis. Deregulated E2F activity is tolerated in cancer cells due to inactivation of the ARF-p53 pathway, thus representing a feature unique to cancer cells. Deregulated E2F activity, which activates tumor suppressor genes, is distinct from enhanced E2F activity, which activates growth-related genes, in that deregulated E2F activity does not depend on the heterodimeric partner DP. Indeed, the ARF promoter, which is specifically activated by deregulated E2F, showed higher cancer-cell specific activity, compared to the E2F1 promoter, which is also activated by E2F induced by growth stimulation. Thus, deregulated E2F activity is an attractive potential therapeutic tool to specifically target cancer cells.
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18
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Long Non-Coding RNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15010303. [PMID: 36612299 PMCID: PMC9818929 DOI: 10.3390/cancers15010303] [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: 12/07/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of cancer. In this study, to understand the significance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), which is a major aberrant signaling pathway in pancreatic cancer, for the expression of lncRNAs, we performed comparative transcriptome analyses between pancreatic cancer cell lines with or without activation of MAPK. We identified 45 lncRNAs presumably associated with MAPK in pancreatic cancer cells; among these, LINC00941 was consistently upregulated by MAPK. The immediate genomic upstream region flanking LINC00941 was identified as a promoter region, the activity of which was found to be preferentially associated with MAPK activity via ETS-1 binding site. LINC00941 promoted cell proliferation in vitro. Moreover, TCGA data analysis indicated that high expression of LINC00941 was associated with poor prognosis of patients with pancreatic cancer. Transcriptomes comparing transcriptions between cells with and without LINC00941 knockdown revealed 3229 differentially expressed genes involved in 44 biological processes, including the glycoprotein biosynthetic process, beta-catenin-TCF complex assembly, and histone modification. These results indicate that MAPK mediates the aberrant expression of lncRNAs. LINC00941 is the lncRNA by MAPK most consistently promoted, and is implicated in the dismal prognosis of pancreatic cancer. MAPK-associated lncRNAs may play pivotal roles in malignant phenotypes of pancreatic cancer, and as such might represent both potentially valid therapeutic targets and diagnostic biomarkers.
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19
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Zhang Y, Lyu L, Wang W, Zhang L. High expression of E2F transcription factors 7: An independent predictor of poor prognosis in patients with lung adenocarcinoma. Medicine (Baltimore) 2022; 101:e29253. [PMID: 35984189 PMCID: PMC9388032 DOI: 10.1097/md.0000000000029253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Adenocarcinoma is the most common pathological type of lung cancer. The E2F7 transcription factor has been confirmed to be related to the occurrence and development of a variety of solid tumors, but the relationship with the prognosis of lung cancer is still unclear. Therefore, we conducted this study to explore the prognostic value of E2F7 for lung adenocarcinoma (LUAD) patients. In this study, we analyzed samples from the Cancer Genome Atlas (TCGA) to study the correlation between the expression of E2F7 and clinical features, the difference in expression between tumors and normal tissues, the prognostic and diagnostic value, and Enrichment analysis of related genes. All statistical analysis uses R statistical software (version 3.6.3). The result shows that the expression level of E2F7 in LUAD was significantly higher than that of normal lung tissue (P = 1e-34). High expression of E2F7 was significantly correlated with gender (P = .034), pathologic stage (P = .046) and M stage (P = .025). Multivariate Cox analysis confirmed that E2F7 is an independent risk factor for OS in LUAD patients (P = .027). Genes related to cell cycle checkpoints, DNA damage telomere stress-induced senescence, DNA methylation, chromosome maintenance and mitotic prophase showed differential enrichment in the E2F7 high expression group. In short, high expression of E2F7 is an independent risk factor for OS in LUAD patients and has a high diagnostic value.
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Affiliation(s)
- Yu Zhang
- Xinjiang Medical University, Department of thoracic surgery, Feicheng Hospital Affiliated to Shandong First Medical University, China
| | - Lan Lyu
- Department of Plastic Surgery, Feicheng Hospital Affiliated to Shandong First Medical University, China
| | - Wei Wang
- Department of Expert's Outpatient, Feicheng Hospital Affiliated to Shandong First Medical University, China
| | - Liwei Zhang
- Xinjiang Medical University, China
- *Correspondence: Liwei Zhang, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China, 830054, China (e-mail: )
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20
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Gutierrez C. A Journey to the Core of the Plant Cell Cycle. Int J Mol Sci 2022; 23:8154. [PMID: 35897730 PMCID: PMC9330084 DOI: 10.3390/ijms23158154] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/16/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Production of new cells as a result of progression through the cell division cycle is a fundamental biological process for the perpetuation of both unicellular and multicellular organisms. In the case of plants, their developmental strategies and their largely sessile nature has imposed a series of evolutionary trends. Studies of the plant cell division cycle began with cytological and physiological approaches in the 1950s and 1960s. The decade of 1990 marked a turn point with the increasing development of novel cellular and molecular protocols combined with advances in genetics and, later, genomics, leading to an exponential growth of the field. In this article, I review the current status of plant cell cycle studies but also discuss early studies and the relevance of a multidisciplinary background as a source of innovative questions and answers. In addition to advances in a deeper understanding of the plant cell cycle machinery, current studies focus on the intimate interaction of cell cycle components with almost every aspect of plant biology.
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Affiliation(s)
- Crisanto Gutierrez
- Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Nicolas Cabrera 1, Cantoblanco, 28049 Madrid, Spain
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21
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Schulze M, Kumar Y, Rattay M, Niemann J, Wijffels RH, Martens D. Transcriptomic analysis reveals mode of action of butyric acid supplementation in an intensified CHO cell fed‐batch process. Biotechnol Bioeng 2022; 119:2359-2373. [PMID: 35641884 PMCID: PMC9545226 DOI: 10.1002/bit.28150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/17/2022] [Accepted: 05/28/2022] [Indexed: 11/10/2022]
Abstract
Process intensification is increasingly used in the mammalian biomanufacturing industry. The key driver of this trend is the need for more efficient and flexible production strategies to cope with the increased demand for biotherapeutics predicted in the next years. Therefore, such intensified production strategies should be designed, established, and characterized. We established a CHO cell process consisting of an intensified fed‐batch (iFB), which is inoculated by an N‐1 perfusion process that reaches high cell concentrations (100 × 106 c ml−1). We investigated the impact of butyric acid (BA) supplementation in this iFB process. Most prominently, higher cellular productivities of more than 33% were achieved, thus 3.5 g L−1 of immunoglobulin G (IgG) was produced in 6.5 days. Impacts on critical product quality attributes were small. To understand the biological mechanisms of BA in the iFB process, we performed a detailed transcriptomic analysis. Affected gene sets reflected concurrent inhibition of cell proliferation and impact on histone modification. These translate into subsequently enhanced mechanisms of protein biosynthesis: enriched regulation of transcription, messenger RNA processing and transport, ribosomal translation, and cellular trafficking of IgG intermediates. Furthermore, we identified mutual tackling points for optimization by gene engineering. The presented strategy can contribute to meet future requirements in the continuously demanding field of biotherapeutics production.
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Affiliation(s)
- Markus Schulze
- Product Development Cell Culture Technologies, Sartorius Stedim Biotech GmbHAugust‐Spindler‐Str. 1137079GöttingenGermany
- Bioprocess EngineeringWageningen UniversityPO Box 166700 AAWageningenNetherlands
| | - Yadhu Kumar
- Eurofins Genomics Europe Sequencing GmbHJakob‐Stadler‐Platz 7D‐78467KonstanzGermany
| | - Merle Rattay
- Corporate Research Advanced Cell Biology, Sartorius Stedim Cellca GmbHMarie‐Goeppert‐Mayer‐Str. 989081Ulm
| | - Julia Niemann
- Corporate Research BioProcessing Upstream, Sartorius Stedim Biotech GmbHAugust‐Spindler‐Str. 1137079GöttingenGermany
| | - Rene H. Wijffels
- Bioprocess EngineeringWageningen UniversityPO Box 166700 AAWageningenNetherlands
- Biosciences and AquacultureNord UniversityN‐8049BodøNorway
| | - Dirk Martens
- Bioprocess EngineeringWageningen UniversityPO Box 166700 AAWageningenNetherlands
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22
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Transcription Factors with Targeting Potential in Gliomas. Int J Mol Sci 2022; 23:ijms23073720. [PMID: 35409080 PMCID: PMC8998804 DOI: 10.3390/ijms23073720] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 12/18/2022] Open
Abstract
Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.
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23
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An Apple a Day Keeps the Doctor Away: Potential Role of miRNA 146 on Macrophages Treated with Exosomes Derived from Apples. Biomedicines 2022; 10:biomedicines10020415. [PMID: 35203624 PMCID: PMC8962404 DOI: 10.3390/biomedicines10020415] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/02/2022] [Accepted: 02/06/2022] [Indexed: 12/12/2022] Open
Abstract
The constant dialogue between the plant world and the animal world (including man among them) has been known since the time of Adam and Eve, where an apple was the origin of the evils of the world. Apart from Snow White—who might have something to object to when it comes to the use of apples—fruits, plants, and natural extracts have been known for millennia as remedies for human health-related ailments. In the light of such evidence, the aim of the present work was to investigate from a biological point of view the potential role of apple exosomes in inflammatory processes on human cells. To this end we isolated and characterized apple exosomes and treated human cells such as macrophages and NCTC L929 as cancer cells in order to evaluate the tumorigenic and anti-inflammatory effect of apple exomes. Microscopic and molecular biology analyses were conducted to characterize exosomes and to assess cell proliferation, death, and miRNA line, as well as gene expression and the uptake of exosomes by cells. The results confirm the absolute biological safety of exosomes and their anti-inflammatory effect, mediated mainly by miRNA146 production by M2 macrophages.
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24
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Zhang ZM, Cao HB, Li ZH, Zhuo R, Tao YF, Li XL, Li G, Liao XM, Fang F, Xie Y, Wu D, Wang HR, Wang JW, Chen YL, Yu JJ, Jia SQ, Yang RD, Guo XY, Yang Y, Feng CX, Xu YY, Qian GH, Pan J. SAPCD2 promotes neuroblastoma progression by altering the subcellular distribution of E2F7. Cell Death Dis 2022; 13:174. [PMID: 35197448 PMCID: PMC8866461 DOI: 10.1038/s41419-022-04624-z] [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: 10/27/2021] [Revised: 01/23/2022] [Accepted: 02/07/2022] [Indexed: 11/16/2022]
Abstract
Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.
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25
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Chen TR, Cao HM, Wu Y, Xie JT, Lan HF, Jin LN. PHOSPHO1 Serves as a Key Metabolism-Related Biomarker in the Tumorigenesis of Diffuse Large B-cell Lymphoma. Curr Med Sci 2022; 42:754-768. [PMID: 35943680 PMCID: PMC9362366 DOI: 10.1007/s11596-022-2612-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/29/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Due to its genetic heterogeneity and abnormal metabolism, many DLBCL patients have a poor prognosis. This study investigated the key metabolism-related genes and potential mechanisms. METHODS Differentially expressed genes, differentially expressed transcription factors (TFs), and differentially expressed metabolism-related genes (DEMRGs) of glucose and lipid metabolic processes were identified using the edgeR package. Key DEMRGs were screened by Lasso regression, and a prediction model was constructed. The cell type identification by estimating relative subsets of RNA transcripts algorithm was utilized to assess the fraction of immune cells, and Gene Set Enrichment Analysis was used to determine immune-related pathways. A regulatory network was constructed with significant co-expression interactions among TFs, DEMRGs, immune cells/pathways, and hallmark pathways. RESULTS A total of 1551 DEMRGs were identified. A prognostic model with a high applicability (area under the curve=0.921) was constructed with 13 DEMRGs. Tumorigenesis of DLBCL was highly related to the neutrophil count. Four DEMRGs (PRXL2AB, CCN1, DECR2 and PHOSPHO1) with 32 TF-DEMRG, 36 DEMRG-pathway, 14 DEMRG-immune-cell, 9 DEMRG-immune-gene-set, and 67 DEMRG-protein-chip interactions were used to construct the regulatory network. CONCLUSION We provided a prognostic prediction model based on 13 DEMRGs for DLBCL. We found that phosphatase, orphan 1 (PHOSPHO1) is positively regulated by regulatory factor X5 (RFX5) and mediates MYC proto-oncogene (MYC) targeting the V2 pathway and neutrophils.
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Affiliation(s)
- Tian-Rui Chen
- Department of Medicine, Shanghai Di An Medical Laboratory Co., Ltd, Shanghai, 200433, China
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Huang-Ming Cao
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Yin Wu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Jiang-Tao Xie
- Department of Medicine, Shanghai Di An Medical Laboratory Co., Ltd, Shanghai, 200433, China
| | - Hai-Feng Lan
- Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Li-Na Jin
- Department of Hematology, Myeloma & Lymphoma Center, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
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26
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Chu X, Wang W, Sun Z, Bao F, Feng L. An N 6-methyladenosine and target genes-based study on subtypes and prognosis of lung adenocarcinoma. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:253-270. [PMID: 34902990 DOI: 10.3934/mbe.2022013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Purpose: Lung adenocarcinoma (LUAD) is a highly lethal subtype of primary lung cancer with a poor prognosis. N6-methyladenosine (m6A), the most predominant form of RNA modification, regulates biological processes and has critical prognostic implications for LUAD. Our study aimed to mine potential target genes of m6A regulators to explore their biological significance in subtyping LUAD and predicting survival. Methods: Using gene expression data from TCGA database, candidate target genes of m6A were predicted from differentially expressed genes (DEGs) in tumor based on M6A2 Target database. The survival-related target DEGs identified by Cox-regression analysis was used for consensus clustering analysis to subtype LUAD. Uni-and multi-variable Cox regression analysis and LASSO Cox-PH regression analysis were used to select the optimal prognostic genes for constructing prognostic score (PS) model. Nomogram encompassing PS score and independent prognostic factors was built to predict 3-year and 5-year survival probability. Results: We obtained 2429 DEGs in tumor tissue, within which, 1267 were predicted to m6A target genes. A prognostic m6A-DEGs network of 224 survival-related target DEGs was established. We classified LUAD into 2 subtypes, which were significantly different in OS time, clinicopathological characteristics, and fractions of 12 immune cell types. A PS model of five genes (C1QTNF6, THSD1, GRIK2, E2F7 and SLCO1B3) successfully split the training set or an independent GEO dataset into two subgroups with significantly different OS time (p < 0.001, AUC = 0.723; p = 0.017, AUC = 0.705).A nomogram model combining PS status, pathologic stage, and recurrence was built, showing good performance in predicting 3-year and 5-year survival probability (C-index = 0.708, 0.723, p-value = 0). Conclusion: Using candidate m6A target genes, we obtained two molecular subtypes and designed a reliable five-gene PS score model for survival prediction in LUAD.
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Affiliation(s)
- Xiao Chu
- Department of Thoracic Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Weiqing Wang
- Department of Thoracic Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Zhaoyun Sun
- Department of Thoracic Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Feichao Bao
- Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Chest Hospital, Shanghai, China
| | - Liang Feng
- Department of Thoracic Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
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27
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Xu F, Tang Q, Wang Y, Wang G, Qian K, Ju L, Xiao Y. Development and Validation of a Six-Gene Prognostic Signature for Bladder Cancer. Front Genet 2021; 12:758612. [PMID: 34938313 PMCID: PMC8685517 DOI: 10.3389/fgene.2021.758612] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022] Open
Abstract
Human bladder cancer (BCa) is the most common urogenital system malignancy. Patients with BCa have limited treatment efficacy in clinical practice. Novel biomarkers could provide more crucial information conferring to cancer diagnosis, treatment, and prognosis. Here, we aimed to explore and identify novel biomarkers associated with cancer-specific survival of patients with BCa to build a prognostic signature. Based on univariate Cox regression, Lasso regression, and multivariate Cox regression analysis, we conducted an integrated analysis in the training set (GSE32894) and established a six-gene signature to predict the cancer-specific survival for human BCa. The six genes were Cyclin Dependent Kinase 4 (CDK4), E2F Transcription Factor 7 (E2F7), Collagen Type XI Alpha 1 Chain (COL11A1), Bradykinin Receptor B2 (BDKRB2), Yip1 Interacting Factor Homolog B (YIF1B), and Zinc Finger Protein 415 (ZNF415). Then, we validated the prognostic value of the model by using two other datasets (GSE13507 and TCGA). Also, we conducted univariate and multivariate Cox regression analyses, and results indicated that the six-gene signature was an independent prognostic factor of cancer-specific survival of patients with BCa. Functional analysis was performed based on the differentially expressed genes of low- and high-risk patients, and we found that they were enriched in lipid metabolic and cell division-related biological processes. Meanwhile, the gene set enrichment analysis (GSEA) revealed that high-risk samples were enriched in cell cycle and cancer-related pathways [G2/M checkpoint, E2F targets, mitotic spindle, mTOR signaling, spermatogenesis, epithelial–mesenchymal transition (EMT), DNA repair, PI3K/AKT/mTOR signaling, unfolded protein response (UPR), and MYC targets V2]. Lastly, we detected the relative expression of each signature in BCa cell lines by quantitative real-time PCR (qRT-PCR). As far as we know, currently, the present study is the first research that developed and validated a cancer-specific survival prognostic index based on three independent cohorts. The results revealed that this six-gene signature has a predictive ability for cancer-specific prognosis. Moreover, we also verified the relative expression of these six signatures between the bladder cell line and four BCa cell lines by qRT-PCR. Nevertheless, experiments to further explore the function of six genes are lacking.
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Affiliation(s)
- Fei Xu
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qianqian Tang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yejinpeng Wang
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Wang
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Kaiyu Qian
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Lingao Ju
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Yu Xiao
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
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28
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Sladky VC, Eichin F, Reiberger T, Villunger A. Polyploidy control in hepatic health and disease. J Hepatol 2021; 75:1177-1191. [PMID: 34228992 DOI: 10.1016/j.jhep.2021.06.030] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/25/2021] [Accepted: 06/15/2021] [Indexed: 12/24/2022]
Abstract
A balanced increase in DNA content (ploidy) is observed in some human cell types, including bone-resorbing osteoclasts, platelet-producing megakaryocytes, cardiomyocytes or hepatocytes. The impact of increased hepatocyte ploidy on normal physiology and diverse liver pathologies is still poorly understood. Recent findings suggest swift genetic adaptation to hepatotoxic stress and the protection from malignant transformation as beneficial effects. Herein, we discuss the molecular mechanisms regulating hepatocyte polyploidisation and its implication for different liver diseases and hepatocellular carcinoma. We report on centrosomes' role in limiting polyploidy by activating the p53 signalling network (via the PIDDosome multiprotein complex) and we discuss the role of this pathway in liver disease. Increased hepatocyte ploidy is a hallmark of hepatic inflammation and may play a protective role against liver cancer. Our evolving understanding of hepatocyte ploidy is discussed from the perspective of its potential clinical application for risk stratification, prognosis, and novel therapeutic strategies in liver disease and hepatocellular carcinoma.
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Affiliation(s)
- Valentina C Sladky
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Felix Eichin
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
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29
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Pillai VV, Koganti PP, Kei TG, Gurung S, Butler WR, Selvaraj V. Efficient induction and sustenance of pluripotent stem cells from bovine somatic cells. Biol Open 2021; 10:272681. [PMID: 34719702 PMCID: PMC8565620 DOI: 10.1242/bio.058756] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Although derivation of naïve bovine embryonic stem cells is unachieved, the possibility for generation of bovine induced pluripotent stem cells (biPSCs) has been generally reported. However, attempts to sustain biPSCs by promoting self-renewal have not been successful. Methods established for maintaining murine and human induced pluripotent stem cells (iPSCs) do not support self-renewal of iPSCs for any bovid species. In this study, we examined methods to enhance complete reprogramming and concurrently investigated signaling relevant to pluripotency of the bovine blastocyst inner cell mass (ICM). First, we identified that forced expression of SV40 large T antigen together with the reprogramming genes (OCT4, SOX2, KLF4 and MYC) substantially enhanced the reprogramming efficacy of bovine fibroblasts to biPSCs. Second, we uncovered that TGFβ signaling is actively perturbed in the ICM. Inhibition of ALK4/5/7 to block TGFβ/activin/nodal signaling together with GSK3β and MEK1/2 supported robust in vitro self-renewal of naïve biPSCs with unvarying colony morphology, steady expansion, expected pluripotency gene expression and committed differentiation plasticity. Core similarities between biPSCs and stem cells of the 16-cell-stage bovine embryo indicated a stable ground state of pluripotency; this allowed us to reliably gain predictive understanding of signaling in bovine pluripotency using systems biology approaches. Beyond defining a high-fidelity platform for advancing biPSC-based biotechnologies that have not been previously practicable, these findings also represent a significant step towards understanding corollaries and divergent aspects of bovine pluripotency. This article has an associated First Person interview with the joint first authors of the paper. Summary: Pluripotency reprogramming by overcoming the stable epigenome of bovine cells, and uncovering precise early embryo self-renewal mechanisms enables sustenance and expansion of authentic induced pluripotent stem cells in vitro.
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Affiliation(s)
- Viju Vijayan Pillai
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
| | - Prasanthi P Koganti
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
| | - Tiffany G Kei
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
| | - Shailesh Gurung
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
| | - W Ronald Butler
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
| | - Vimal Selvaraj
- Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY14853, USA
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30
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Zhang S, Long F, Lin H, Wang X, Jiang G, Wang T. Regulatory roles of phytochemicals on circular RNAs in cancer and other chronic diseases. Pharmacol Res 2021; 174:105936. [PMID: 34653635 DOI: 10.1016/j.phrs.2021.105936] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/28/2021] [Accepted: 10/08/2021] [Indexed: 12/26/2022]
Abstract
As novel non-coding RNAs (ncRNAs), circular RNAs (circRNAs) play an essential role in the pathogenesis of many chronic diseases, and the regulation of these functional molecules has become a research hotspot gradually. Within the past decade, phytochemicals were reported to regulate the expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in various chronic diseases, and more recently, most studies focus on the regulatory roles of phytochemicals on circRNAs. Abnormal expression of circRNAs has been identified in chronic diseases like cancer, heart failure, depression and atherosclerosis, and numerous studies have revealed the modulation of circRNAs by phytochemicals including berberine, celastrol, cinnamaldehyde, curcumin, et al. The expression of circRNAs, such as circSATB2 and circFOXM1, were modulated by phytochemicals, and these regulations further affected cell proliferation, apoptosis, migration, invasion, autophagy, chemosensitivity, radiosensitivity and other biological processes. Mechanismly, the circRNAs mainly functioned as miRNA sponge, subsequently affecting miRNA-mediated regulation of target genes and related cell signaling pathways. In this review, we summarized the impact of phytochemicals on circRNAs expression and biological function, and discussed the mechanisms underlying phytochemicals regulating circRNAs in cancer and other chronic diseases.
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Affiliation(s)
- Shasha Zhang
- Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Hong Lin
- Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xi Wang
- Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Gang Jiang
- Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Wang
- Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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31
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Xie D, Pei Q, Li J, Wan X, Ye T. Emerging Role of E2F Family in Cancer Stem Cells. Front Oncol 2021; 11:723137. [PMID: 34476219 PMCID: PMC8406691 DOI: 10.3389/fonc.2021.723137] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/27/2021] [Indexed: 12/14/2022] Open
Abstract
The E2F family of transcription factors (E2Fs) consist of eight genes in mammals. These genes encode ten proteins that are usually classified as transcriptional activators or transcriptional repressors. E2Fs are important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis, the DNA damage response and apoptosis. A growing body of evidence demonstrates that cancer stem cells (CSCs) are key players in tumor development, metastasis, drug resistance and recurrence. This review focuses on the role of E2Fs in CSCs and notes that many signals can regulate the activities of E2Fs, which in turn can transcriptionally regulate many different targets to contribute to various biological characteristics of CSCs, such as proliferation, self-renewal, metastasis, and drug resistance. Therefore, E2Fs may be promising biomarkers and therapeutic targets associated with CSCs pathologies. Finally, exploring therapeutic strategies for E2Fs may result in disruption of CSCs, which may prevent tumor growth, metastasis, and drug resistance.
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Affiliation(s)
- Dan Xie
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Qin Pei
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Jingyuan Li
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Xue Wan
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Ting Ye
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
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32
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Katsanos D, Ferrando-Marco M, Razzaq I, Aughey G, Southall TD, Barkoulas M. Gene expression profiling of epidermal cell types in C. elegans using Targeted DamID. Development 2021; 148:dev199452. [PMID: 34397094 PMCID: PMC7613258 DOI: 10.1242/dev.199452] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 08/05/2021] [Indexed: 12/19/2022]
Abstract
The epidermis of Caenorhabditis elegans is an essential tissue for survival because it contributes to the formation of the cuticle barrier as well as facilitating developmental progression and animal growth. Most of the epidermis consists of the hyp7 hypodermal syncytium, the nuclei of which are largely generated by the seam cells, which exhibit stem cell-like behaviour during development. How seam cell progenitors differ transcriptionally from the differentiated hypodermis is poorly understood. Here, we introduce Targeted DamID (TaDa) in C. elegans as a method for identifying genes expressed within a tissue of interest without cell isolation. We show that TaDa signal enrichment profiles can be used to identify genes transcribed in the epidermis and use this method to resolve differences in gene expression between the seam cells and the hypodermis. Finally, we predict and functionally validate new transcription and chromatin factors acting in seam cell development. These findings provide insights into cell type-specific gene expression profiles likely associated with epidermal cell fate patterning.
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Affiliation(s)
- Dimitris Katsanos
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Mar Ferrando-Marco
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Iqrah Razzaq
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Gabriel Aughey
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Tony D. Southall
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Michalis Barkoulas
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
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33
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Fischietti M, Eckerdt F, Blyth GT, Arslan AD, Mati WM, Oku CV, Perez RE, Lee-Chang C, Kosciuczuk EM, Saleiro D, Beauchamp EM, Lesniak MS, Verzella D, Sun L, Fish EN, Yang GY, Qiang W, Platanias LC. Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma. Oncogene 2021; 40:3273-3286. [PMID: 33846574 PMCID: PMC8106654 DOI: 10.1038/s41388-021-01761-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 03/04/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
We provide evidence that a member of the human Schlafen (SLFN) family of proteins, SLFN5, is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Targeted deletion of SLFN5 results in decreased PDAC cell proliferation and suppresses PDAC tumorigenesis in in vivo PDAC models. Importantly, high expression levels of SLFN5 correlate with worse outcomes in PDAC patients, implicating SLFN5 in the pathophysiology of PDAC that leads to poor outcomes. Our studies establish novel regulatory effects of SLFN5 on cell cycle progression through binding/blocking of the transcriptional repressor E2F7, promoting transcription of key genes that stimulate S phase progression. Together, our studies suggest an essential role for SLFN5 in PDAC and support the potential for developing new therapeutic approaches for the treatment of pancreatic cancer through SLFN5 targeting.
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Affiliation(s)
- Mariafausta Fischietti
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Frank Eckerdt
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Gavin T Blyth
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ahmet D Arslan
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - William M Mati
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Chidera V Oku
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ricardo E Perez
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Catalina Lee-Chang
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ewa M Kosciuczuk
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Diana Saleiro
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Elspeth M Beauchamp
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Maciej S Lesniak
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Daniela Verzella
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Leyu Sun
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Eleanor N Fish
- Toronto General Hospital Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Guang-Yu Yang
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Wenan Qiang
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA
| | - Leonidas C Platanias
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
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Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context. Cancers (Basel) 2021; 13:cancers13092033. [PMID: 33922435 PMCID: PMC8122802 DOI: 10.3390/cancers13092033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 11/24/2022] Open
Abstract
Simple Summary In virtually all human malignancies, the CDK-RB-E2F pathway is dysregulated resulting in the activation of the E2F transcriptional network. Rb and atypical E2Fs are the most important negative regulators of E2F-dependent transcription during tumorigenesis. However, it is unknown whether they cooporate or act independently in tumor development. Here we show that combined loss of RB and atypical E2Fs in mice enhances tumorigenesis in the liver, while in the pituitary gland, we observe inhibition of tumorigenesis. These findings suggest that the interaction between RB and atypical E2Fs in controlling tumorigenesis occurs in a tissue cell-type specific manner. Abstract E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/− mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.
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Zhou P, Xiao L, Xu X. Identification of E2F transcription factor 7 as a novel potential biomarker for oral squamous cell carcinoma. Head Face Med 2021; 17:7. [PMID: 33637098 PMCID: PMC7908640 DOI: 10.1186/s13005-021-00258-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 02/05/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND As a tumor-accelerating transcriptional factor, E2F transcription factor 7 (E2F7) was up-regulated in many forms of cancers. Nevertheless, little has been reported about the impacts of E2F7 on oral squamous cell carcinoma (OSCC). Here, we aimed to probe whether E2F7 had influences on OSCC and its potential mechanism. METHODS The expression of E2F7 in OSCC tissues was analyzed using the data acquired from TCGA and ONCOMINE databases. E2F7 prognostic value in OSCC patients was analyzed utilizing TCGA database. The expression of E2F7 in OSCC cell lines was detected by qRT-PCR. Gain-and loss-function of E2F7 assays in TCA-83 and CAL27 cells were performed respectively to inquire the function of E2F7. Western blotting was applied to test the alternations of EMT-related markers. RESULTS In OSCC tissues, E2F7 was highly expressed. Besides, high expression of E2F7 predicted worse prognosis in OSCC patients. Moreover, E2F7 was over-expressed in TCA-83, HSC-4 and CAL27 (all OSCC cell lines) cells relative to that in HNOK (a normal cell line) cells. Gain-and loss-function assays displayed that deficiency of E2F7 suppresses CAL27 cell growth, migration, invasion and E2F7 high-expression resulted in inverse outcomes in TCA-83 cells. Finally, we found that silencing of E2F7 facilitated E-cadherin protein expression level and reduced N-cadherin, Vimentin and Snail protein levels in CAL27 cells, whilst E2F7 high-expression exhibited the opposite effects in TCA-83 cells. CONCLUSIONS These outcomes indicated that E2F7 performs a carcinogenic role in OSCC, which provides a theoretical basis for the therapeutic strategies of OSCC.
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Affiliation(s)
- Ping Zhou
- Department of Stomatology, Jining No.1 People's Hospital, Jining, 272000, Shandong, China
| | - Lei Xiao
- Department of Stomatology, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China
| | - Xiaonan Xu
- Department of Stomatology, Jining No.1 People's Hospital, Jining, 272000, Shandong, China.
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Wang Y, Wo Y, Lu T, Sun X, Liu A, Dong Y, Du W, Su W, Huang Z, Jiao W. Circ-AASDH functions as the progression of early stage lung adenocarcinoma by targeting miR-140-3p to activate E2F7 expression. Transl Lung Cancer Res 2021; 10:57-70. [PMID: 33569293 PMCID: PMC7867743 DOI: 10.21037/tlcr-20-1062] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Lung adenocarcinoma (LUAD), which is the most common subtype of non-small cell lung cancer, is a leading course of cancer-related mortality worldwide. Recently, circular RNA (CircRNAs) has become a hot spot in cancer research because of its important role in tumorigenesis and development and its superior stability. This study aims to clarify the role of circ-AASDH in LUAD and explore its competitive endogenous RNA mechanism. Methods The circ-AASDH, miR-140-3p and E2F transcription factor 7 (E2F7) mRNA expression levels were detected via qRT-PCR. CCK-8 and colony formation assay were used to evaluate the ability of cell proliferation. Transwell assay and wound healing assay were performed to measure the invasion and migration ability. Flow cytometry was used to detect the apoptosis of cells. Moreover, Sanger sequencing, RNaseR treatment and divergent primers were used to verify the circular structure. Luciferase reporter and RNA pull-down experiment were performed to characterize the ceRNA mechanism of circ-AASDH. The xenograft model of mice was established to investigate the tumorigenicity of circ-AASDH to LUAD in vivo. Results By screening for differentially expressed circRNAs, we found that circ-AASDH was highly expressed in LUAD tissues and cells and correlated with tumor size, clinical stage and poor prognosis. Transfection of si-circ-AASDH can inhibit the proliferation and migration of LUAD cells and promote apoptosis in vitro. In mechanism, circ-AASDH could be used as a sponge of miR-140-3p to weaken its inhibition on the expression of E2F7. Additionally, the overexpression of circ-AASDH could deduce the suppression of miR-140-3p on the malignant progression of LUAD cells. Besides, silencing of circ-AASDH inhibited cell proliferation and migration by regulating the expression of E2F7. Furthermore, overexpression of circ-AASDH can promote the growth of LUAD in vivo. Conclusions Circ-AASDH/miR-140-3p/E2F7 regulating axis promoted the progression in LUAD. Our results provided ideas for understanding the biological mechanism of circ-AASDH and clarify potential therapeutic targets in LUAD.
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Affiliation(s)
- Yuanyong Wang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yang Wo
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tong Lu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao Sun
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ao Liu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanting Dong
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenxing Du
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenhao Su
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhangfeng Huang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjie Jiao
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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Moreno E, Toussaint MJ, van Essen SC, Bongiovanni L, van Liere EA, Koster MH, Yuan R, van Deursen JM, Westendorp B, de Bruin A. E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice. Hepatology 2021; 73:303-317. [PMID: 32259305 PMCID: PMC7898887 DOI: 10.1002/hep.31259] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 03/12/2020] [Accepted: 03/19/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Up-regulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. APPROACH AND RESULTS Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine-induced liver tumors. CONCLUSION Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.
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Affiliation(s)
- Eva Moreno
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Mathilda J.M. Toussaint
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Saskia C. van Essen
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Laura Bongiovanni
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Elsbeth A. van Liere
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Mirjam H. Koster
- Division Molecular GeneticsDepartment of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Ruixue Yuan
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands,Department of PathologyAcademic Medical CenterAmsterdamthe Netherlands
| | - Jan M. van Deursen
- Department of Biochemistry and Molecular BiologyMayo ClinicRochesterMN,Department of Pediatric and Adolescent MedicineMayo ClinicRochesterMN
| | - Bart Westendorp
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands
| | - Alain de Bruin
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtthe Netherlands,Division Molecular GeneticsDepartment of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
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Chen X, Wang D, Sun B, Liu C, Zhu K, Zhang A. GBE attenuates arsenite-induced hepatotoxicity by regulating E2F1-autophagy-E2F7a pathway and restoring lysosomal activity. J Cell Physiol 2020; 236:4050-4065. [PMID: 33174204 DOI: 10.1002/jcp.30147] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/15/2020] [Accepted: 10/27/2020] [Indexed: 11/07/2022]
Abstract
Arsenic is an environmental toxicant. Its overdose can cause liver damage. Autophagy has been reported to be involved in arsenite (iAs3+ ) cytotoxicity and plays a dual role in cell proliferation and cell death. However, the effect and molecular regulative mechanisms of iAs3+ on autophagy in hepatocytes remains largely unknown. Here, we found that iAs3+ exposure lead to hepatotoxicity by inducing autophagosome and autolysosome accumulation. On the one hand, iAs3+ promoted autophagosome synthesis by inhibiting E2F1/mTOR pathway in L-02 human hepatocytes. On the other, iAs3+ blocked autophagosome degradation partially via suppressing the expression of INPP5E and Rab7 as well as impairing lysosomal activity. More importantly, autophagosome and autolysosome accumulation induced by iAs3+ increased the protein level of E2F7a, which could further inhibit cell viability and induce apoptosis of L-02 cells. The treatment of Ginkgo biloba extract (GBE) effectively reduced autophagosome and autolysosome accumulation and thus alleviated iAs3+ -induced hepatotoxicity. Moreover, GBE could also protect lysosomal activity, promote the phosphorylation level of E2F1 (Ser364 and Thr433) and Rb (Ser780) as well as suppress the protein level of E2F7a in iAs3+ -treated L-02 cells. Taken together, our data suggested that autophagosome and autophagolysosome accumulation play a critical role for iAs3+ -induced hepatotoxicity, and GBE is a promising candidate for intervening iAs3+ induced liver damage by regulating E2F1-autophagy-E2F7a pathway and restoring lysosomal activity.
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Affiliation(s)
- Xiong Chen
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Dapeng Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Baofei Sun
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Chunyan Liu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Kai Zhu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
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Xu C, Qi X. MiR-10b inhibits migration and invasion of pancreatic ductal adenocarcinoma via regulating E2F7. J Clin Lab Anal 2020; 34:e23442. [PMID: 32592206 PMCID: PMC7595905 DOI: 10.1002/jcla.23442] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/12/2020] [Accepted: 06/03/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Abnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR-10b in PDAC. METHODS The RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT-PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co-culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual-Luciferase Reporter Assay System and Infinate M200 PRO microplate reader. RESULTS Based on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR-10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR-10b. In subsequent experiments in molecular biology, miR-10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR-10b could inhibit the invasion and migration of PDAC. MiR-10b was confirmed to be by the E2F7 targeting site by dual-luciferase report. Moreover, rescue experiments prove that miR-10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression. CONCLUSION Our results suggest that miR-10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC.
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Affiliation(s)
- Cui Xu
- General Surgery DepartmentShengJing Hospital of China Medical UniversityShenyangChina
| | - Xiangxiu Qi
- General Surgery DepartmentShengJing Hospital of China Medical UniversityShenyangChina
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40
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Yang R, Wang M, Zhang G, Bao Y, Wu Y, Li X, Yang W, Cui H. E2F7-EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression. Br J Cancer 2020; 123:1445-1455. [PMID: 32814835 PMCID: PMC7591888 DOI: 10.1038/s41416-020-01032-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/24/2020] [Accepted: 07/27/2020] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND E2F transcription factors are considered to be important drivers of tumour growth. E2F7 is an atypical E2F factor, and its role in glioblastoma remains undefined. METHODS E2F7 expression was examined in patients by IHC and qRT-PCR. The overall survival probability was determined by statistical analyses. MTT assay, colony formation, cell-cycle assay, cell metastasis and the in vivo model were employed to determine the functional role of E2F7 in glioblastoma. Chromatin immunoprecipitation, luciferase assay and western blot were used to explore the underlying mechanisms. RESULTS E2F7 was found to be up-regulated in glioblastoma patients, and high E2F7 expression was associated with poor overall survival in glioblastoma patients. Functional studies showed that E2F7 promoted cell proliferation, cell-cycle progression, cell metastasis and tumorigenicity abilities in vitro and in vivo. E2F7 promoted the transcription of EZH2 by binding to its promoter and increased H3K27me3 level. EZH2 recruited H3K27me3 to the promoter of PTEN and inhibited PTEN expression, and then activated the AKT/mTOR signalling pathway. In addition, restored expression of EZH2 recovered the abilities of cell proliferation and metastasis in E2F7-silencing cells. CONCLUSION Collectively, our findings indicate that E2F7 promotes cell proliferation, cell metastasis and tumorigenesis via EZH2-mediated PTEN/AKT/mTOR pathway in glioblastoma.
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Affiliation(s)
- Rui Yang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China. .,State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.
| | - Mei Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Guizhou Provincial College-based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, China
| | - Yonghua Bao
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Yanan Wu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Cancer Center, Medical Research Institute, Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, China
| | - Xiuxiu Li
- Department of Pharmacy, The Second People's Hospital of Liaocheng, Liaocheng, China
| | - Wancai Yang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China.,Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China. .,Cancer Center, Medical Research Institute, Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, China.
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Emanuele MJ, Enrico TP, Mouery RD, Wasserman D, Nachum S, Tzur A. Complex Cartography: Regulation of E2F Transcription Factors by Cyclin F and Ubiquitin. Trends Cell Biol 2020; 30:640-652. [PMID: 32513610 PMCID: PMC7859860 DOI: 10.1016/j.tcb.2020.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023]
Abstract
The E2F family of transcriptional regulators sits at the center of cell cycle gene expression and plays vital roles in normal and cancer cell cycles. Whereas control of E2Fs by the retinoblastoma family of proteins is well established, much less is known about their regulation by ubiquitin pathways. Recent studies placed the Skp1-Cul1-F-box-protein (SCF) family of E3 ubiquitin ligases with the F-box protein Cyclin F at the center of E2F regulation, demonstrating temporal proteolysis of both activator and atypical repressor E2Fs. Importantly, these E2F members, in particular activator E2F1 and repressors E2F7 and E2F8, form a feedback circuit at the crossroads of cell cycle and cell death. Moreover, Cyclin F functions in a reciprocal circuit with the cell cycle E3 ligase anaphase-promoting complex/cyclosome (APC/C), which also controls E2F7 and E2F8. This review focuses on the complex contours of feedback within this circuit, highlighting the deep crosstalk between E2F, SCF-Cyclin F, and APC/C in regulating the oscillator underlying human cell cycles.
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Affiliation(s)
- Michael J Emanuele
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Taylor P Enrico
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ryan D Mouery
- Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Genetics and Molecular Biology Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Danit Wasserman
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Sapir Nachum
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Amit Tzur
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel.
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Pérez-Posada A, Dudin O, Ocaña-Pallarès E, Ruiz-Trillo I, Ondracka A. Cell cycle transcriptomics of Capsaspora provides insights into the evolution of cyclin-CDK machinery. PLoS Genet 2020; 16:e1008584. [PMID: 32176685 PMCID: PMC7098662 DOI: 10.1371/journal.pgen.1008584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 03/26/2020] [Accepted: 12/23/2019] [Indexed: 12/19/2022] Open
Abstract
Progression through the cell cycle in eukaryotes is regulated on multiple levels. The main driver of the cell cycle progression is the periodic activity of cyclin-dependent kinase (CDK) complexes. In parallel, transcription during the cell cycle is regulated by a transcriptional program that ensures the just-in-time gene expression. Many core cell cycle regulators are widely conserved in eukaryotes, among them cyclins and CDKs; however, periodic transcriptional programs are divergent between distantly related species. In addition, many otherwise conserved cell cycle regulators have been lost and independently evolved in yeast, a widely used model organism for cell cycle research. For a better understanding of the evolution of the cell cycle regulation in opisthokonts, we investigated the transcriptional program during the cell cycle of the filasterean Capsaspora owczarzaki, a unicellular species closely related to animals. We developed a protocol for cell cycle synchronization in Capsaspora cultures and assessed gene expression over time across the entire cell cycle. We identified a set of 801 periodic genes that grouped into five clusters of expression over time. Comparison with datasets from other eukaryotes revealed that the periodic transcriptional program of Capsaspora is most similar to that of animal cells. We found that orthologues of cyclin A, B and E are expressed at the same cell cycle stages as in human cells and in the same temporal order. However, in contrast to human cells where these cyclins interact with multiple CDKs, Capsaspora cyclins likely interact with a single ancestral CDK1-3. Thus, the Capsaspora cyclin-CDK system could represent an intermediate state in the evolution of animal-like cyclin-CDK regulation. Overall, our results demonstrate that Capsaspora could be a useful unicellular model system for animal cell cycle regulation.
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Affiliation(s)
- Alberto Pérez-Posada
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Omaya Dudin
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Eduard Ocaña-Pallarès
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Iñaki Ruiz-Trillo
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
- Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Catalonia, Spain
- ICREA, Barcelona, Catalonia, Spain
| | - Andrej Ondracka
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
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Yu H, Li Z, Wang M. Expression and prognostic role of E2F transcription factors in high-grade glioma. CNS Neurosci Ther 2020; 26:741-753. [PMID: 32064771 PMCID: PMC7299000 DOI: 10.1111/cns.13295] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/19/2020] [Accepted: 01/27/2020] [Indexed: 02/06/2023] Open
Abstract
Introduction Patients with high‐grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferation, have been found to be involved in the pathogenesis of various tumor types. Aims To investigate the expression of E2Fs and their prognosis value in high‐grade glioma (HGG). Results Expression of E2Fs was analyzed in 394 HGG samples from TCGA dataset. E2Fs were generally expressed in HGG. Except for E2F3 and E2F5, expression of E2Fs was significantly upregulated and linked with grade progression. E2F1, E2F2, E2F7, and E2F8 were highly correlated with aggressive proliferation oncogenes, as well as potential therapeutic resistance oncogenes. Elevated E2Fs (not E2F3) were associated with adverse tumor features and poorer outcome. E2F7 and E2F8 exhibited superior outcome prediction performance compared with other E2Fs. Additionally, E2F7 and E2F8 independently predicted poorer survival in HGG patients. Gene set enrichment analysis identified a variety of critical oncogenic pathways that were tightly associated with E2F7 or E2F8, including epithelial‐mesenchymal transition, NFκB, STAT3, angiogenesis pathways. Furthermore, elevated expression of E2F7 indicated worse therapeutic response of HGG to irradiation and silencing of E2F7 conferred higher cell‐killing effect when combined with irradiation treatment. Mechanically, E2F7 directly regulates the transcriptional activity of EZH2 via binding at the corresponding promoter area. Conclusions E2Fs (except for E2F3 and E2F5) are highly expressed in HGG and indicate adverse outcome. E2F7 and E2F8 were identified as novel potential prognostic markers in HGG. E2F7 was further validated to be closely associated with radioresistance of HGG and a critical transcriptional regulator of EZH2.
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Affiliation(s)
- Hai Yu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhijin Li
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Maode Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Wan P, Bai X, Yang C, He T, Luo L, Wang Y, Fan M, Wang Z, Lu L, Yin Y, Li S, Guo Q, Song Z. miR-129-5p inhibits proliferation, migration, and invasion in rectal adenocarcinoma cells through targeting E2F7. J Cell Physiol 2020; 235:5689-5701. [PMID: 32052431 DOI: 10.1002/jcp.29501] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 01/09/2020] [Indexed: 12/15/2022]
Abstract
microRNAs (miRNAs), a kind of small noncoding RNAs, are considered able to regulate expression of genes and mediate RNA silencing. miR-129-5p was shown to be a cancer-related miRNA. However, the influence of miR-129-5p in rectal adenocarcinoma (READ) development remains to be determined. Based on the TCGA data, downregulation of miR-129-5p in READ samples was observed. Manual restoration of the miR-129-5p in SW1463 and SW480 cell lines significantly inhibited invasion, migration, and proliferation of READ cell lines, while the apoptosis ability was enhanced. Meanwhile, we found E2F7 acted as a potential target of miR-129-5p and was upregulated in READ samples. E2F7 upregulation reversed the repression of miR-129-5p on READ development. Finally, in vivo experiments showed that inhibition of tumor growth in nude mice was achieved through upregulating miR-129-5p. Overall, our findings suggest increasing of miR-129-5p leads to the suppression of READ progression through regulating the expression of E2F7, which may provide novel insights into the treatment of READ.
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Affiliation(s)
- Ping Wan
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xuan Bai
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Chao Yang
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Tian He
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Lilin Luo
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yun Wang
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Minmin Fan
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Zhilin Wang
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Liming Lu
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yajing Yin
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Sisi Li
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Qiang Guo
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Zhengyi Song
- Department of Digestive System, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan, China
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Construction and Comprehensive Analyses of a Competing Endogenous RNA Network in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5831064. [PMID: 32104698 PMCID: PMC7036093 DOI: 10.1155/2020/5831064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 12/14/2019] [Accepted: 12/26/2019] [Indexed: 12/14/2022]
Abstract
Background Long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) and interact with microRNAs (miRNAs) to regulate target gene expression, which can greatly influence tumor development and progression. Different tumor-node-metastasis (TNM) stages of hepatocellular carcinoma (HCC) defined by the American Joint Committee on Cancer (AJCC) have different clinical results. Our purpose was to comprehensively analyze differentially expressed (DE) lncRNAs, miRNAs, and mRNAs in stage I HCC and identify prognosis-associated RNAs. Methods RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database. A stage I HCC-associated miRNA-lncRNA-mRNA network was constructed. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses of ceRNA-associated DEmRNAs were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 and Clusterprofile in the R package. The protein-protein interaction (PPI) network of the above mRNAs was then constructed using STRING. Finally, the association between lncRNAs and mRNAs in the ceRNA network and prognosis of patients was further analyzed. Linear regression analysis of the above lncRNAs and mRNAs associated with overall survival was performed. Results After a comparison between HCC and adjacent nontumor tissues, 778 lncRNAs, 1608 mRNAs, and 102 miRNAs that were abnormally expressed were identified. The ceRNA network was composed of 56 DElncRNAs, 14 DEmiRNAs, and 30 DEmRNAs. Functional analysis results showed that 30 DEmRNAs were enriched in 14 GO biological process categories and 6 KEGG categories (false discovery rate (FDR) < 0.05). A PPI network was composed of 22 nodes and 58 edges. We detected 4 DElncRNAs (BPESC1, AC061975.6, AC079341.1, and CLLU1) and 6 DEmRNAs (CEP55, E2F1, E2F7, EZH2, G6PD, and SLC7A11) that had significant influences on the overall survival (OS) of stage I HCC patients (P < 0.05). lncRNA BPESC1 was positively correlated with mRNA CEP55 via miR-424, and lncRNA AC061975.6 was positively correlated with mRNA E2F1 via miR-519d. Conclusion Our study identified novel lncRNAs and mRNAs that were associated with the progression and prognosis of stage I HCC and further investigated the regulatory mechanism of lncRNA-mediated ceRNAs in the development of stage I HCC.
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Wasserman D, Nachum S, Cohen M, Enrico TP, Noach-Hirsh M, Parasol J, Zomer-Polak S, Auerbach N, Sheinberger-Chorni E, Nevenzal H, Levi-Dadon N, Wang X, Lahmi R, Michaely E, Gerber D, Emanuele MJ, Tzur A. Cell cycle oscillators underlying orderly proteolysis of E2F8. Mol Biol Cell 2020; 31:725-740. [PMID: 31995441 PMCID: PMC7185961 DOI: 10.1091/mbc.e19-12-0725] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
E2F8 is a transcriptional repressor that antagonizes E2F1 at the crossroads of the cell cycle, apoptosis, and cancer. Previously, we discovered that E2F8 is a direct target of the APC/C ubiquitin ligase. Nevertheless, it remains unknown how E2F8 is dynamically controlled throughout the entirety of the cell cycle. Here, using newly developed human cell-free systems that recapitulate distinct inter-mitotic and G1 phases and a continuous transition from prometaphase to G1, we reveal an interlocking dephosphorylation switch coordinating E2F8 degradation with mitotic exit and the activation of APC/CCdh1. Further, we uncover differential proteolysis rates for E2F8 at different points within G1 phase, accounting for its accumulation in late G1 while APC/CCdh1 is still active. Finally, we demonstrate that the F-box protein Cyclin F regulates E2F8 in G2-phase. Altogether, our data define E2F8 regulation throughout the cell cycle, illuminating an extensive coordination between phosphorylation, ubiquitination and transcription in mammalian cell cycle.
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Affiliation(s)
- Danit Wasserman
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Sapir Nachum
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Meital Cohen
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Taylor P Enrico
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Meirav Noach-Hirsh
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Jasmin Parasol
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Sarit Zomer-Polak
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Naomi Auerbach
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Evelin Sheinberger-Chorni
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Hadas Nevenzal
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Nofar Levi-Dadon
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Xianxi Wang
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Roxane Lahmi
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Efrat Michaely
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Doron Gerber
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Michael J Emanuele
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Amit Tzur
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
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Lafta IJ. E2F6 is essential for cell viability in breast cancer cells during replication stress. ACTA ACUST UNITED AC 2019; 43:293-304. [PMID: 31768102 PMCID: PMC6823915 DOI: 10.3906/biy-1905-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
E2F6 is a member of the E2F family of transcription factors involved in regulation of a wide variety of genes through both activation and repression. E2F6 has been reported as overexpressed in breast cancers but whether or not this is important for tumor development is unclear. We first checked E2F6 expression in tumor cDNAs and the protein level in a range of breast cancer cell lines. RNA interference-mediated depletion was then used to assess the importance of E2F6 expression in cell lines with regard to cell cycle profile using fluorescence-activated cell sorting and a cell survival assay using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The overexpression of E2F6 was confirmed in breast tumor cDNA samples and breast cancer cell lines. Depletion of E2F6 in the breast cancer cells reduced cell viability in MCF-7, T-47D, and MDA-MB-231 cells. There was little effect in the nontumor breast cell line MCF-10A. The deleterious effect on cancer cells was greater during replication stress, leading to an increase in the proportion of breast cancer cells with sub-G1 DNA content. These results suggest that E2F6 might be essential for the survival of breast cancer cells experiencing replication stress, and therefore it could be a target for combined therapy.
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Affiliation(s)
- Inam Jasim Lafta
- Department of Microbiology, College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq
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Circular RNA PRKCI promotes glioma cell progression by inhibiting microRNA-545. Cell Death Dis 2019; 10:616. [PMID: 31409777 PMCID: PMC6692337 DOI: 10.1038/s41419-019-1863-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 07/26/2019] [Accepted: 07/29/2019] [Indexed: 12/12/2022]
Abstract
We here tested expression and potential functions of circular RNA PRKCI (circPRKCI) in human glioma. Our results show that circPRKCI is upregulated in human glioma tissues and glioma cells, correlating with downregulation of its potential target, microRNA-545 (miR-545). In A172 and primary human glioma cells, shRNA-mediated silencing of circPRKCI inhibited cancer cell growth, survival, proliferation, and migration. Conversely, ectopic circPRKCI overexpression promoted A172 cell progression. miR-545 is the primary target of circPRKCI in glioma cells. Forced overexpression of miR-545 mimicked circPRKCI shRNA-induced actions, inhibiting glioma cell survival and proliferation. In contrast, miR-545 inhibition, by a lentiviral antagomiR-545 construct, reversed circPRKCI shRNA-induced anti-A172 cell activity. Importantly, neither circPRKCI shRNA nor circPRKCI overexpression was effective in miR-545-knockout (Cas9 method) A172 cells. Importantly, the subcutaneous and orthotopic A172 xenograft growth was significantly inhibited by circPRKCI silencing. Collectively, circPRKCI promotes human glioma cell progression possibly by inhibiting miR-545. Targeting circPRKCI-miR-545 cascade could efficiently inhibit human glioma cells.
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Mohammadzadeh A, Mirza-Aghazadeh-Attari M, Hallaj S, Saei AA, Alivand MR, Valizadeh A, Yousefi B, Majidinia M. Crosstalk between P53 and DNA damage response in ageing. DNA Repair (Amst) 2019; 80:8-15. [DOI: 10.1016/j.dnarep.2019.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 05/19/2019] [Accepted: 05/22/2019] [Indexed: 02/07/2023]
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Mitxelena J, Apraiz A, Vallejo-Rodríguez J, García-Santisteban I, Fullaondo A, Alvarez-Fernández M, Malumbres M, Zubiaga AM. An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability. Nucleic Acids Res 2019; 46:4546-4559. [PMID: 29590434 PMCID: PMC5961008 DOI: 10.1093/nar/gky218] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 03/15/2018] [Indexed: 12/23/2022] Open
Abstract
The cellular response to DNA damage is essential for maintaining the integrity of the genome. Recent evidence has identified E2F7 as a key player in DNA damage-dependent transcriptional regulation of cell-cycle genes. However, the contribution of E2F7 to cellular responses upon genotoxic damage is still poorly defined. Here we show that E2F7 represses the expression of genes involved in the maintenance of genomic stability, both throughout the cell cycle and upon induction of DNA lesions that interfere with replication fork progression. Knockdown of E2F7 leads to a reduction in 53BP1 and FANCD2 foci and to fewer chromosomal aberrations following treatment with agents that cause interstrand crosslink (ICL) lesions but not upon ionizing radiation. Accordingly, E2F7-depleted cells exhibit enhanced cell-cycle re-entry and clonogenic survival after exposure to ICL-inducing agents. We further report that expression and functional activity of E2F7 are p53-independent in this context. Using a cell-based assay, we show that E2F7 restricts homologous recombination through the transcriptional repression of RAD51. Finally, we present evidence that downregulation of E2F7 confers an increased resistance to chemotherapy in recombination-deficient cells. Taken together, our results reveal an E2F7-dependent transcriptional program that contributes to the regulation of DNA repair and genomic integrity.
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Affiliation(s)
- Jone Mitxelena
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
| | - Aintzane Apraiz
- Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
| | - Jon Vallejo-Rodríguez
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
| | - Iraia García-Santisteban
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
| | - Asier Fullaondo
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
| | - Mónica Alvarez-Fernández
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Marcos Malumbres
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Ana M Zubiaga
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain
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