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Chaturvedi S, Sibi Karthik S, Sadhukhan S, Sonawane A. Unraveling the potential contribution of DHHC2 in cancer biology via untargeted metabolomics. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159593. [PMID: 39788345 DOI: 10.1016/j.bbalip.2025.159593] [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: 06/20/2024] [Revised: 11/01/2024] [Accepted: 01/05/2025] [Indexed: 01/12/2025]
Abstract
DHHC-mediated protein-S-palmitoylation is recognized as a distinct and reversible lipid modification, playing a pivotal role in the progression and prevention of multiple diseases, including cancer and neurodegenerative disorders. Over the past decade, growing evidence indicated the crucial role of DHHC2 in preventing tumorigenesis by palmitoylation of various protein substrates. However, a comprehensive understanding of the specific impact of DHHC2 on cancer cell metabolic regulation remains unclear. To investigate the metabolic changes by DHHC2, we conducted untargeted metabolomic profiling on the HEK-293T cell line with DHHC2-Knockdown (DHHC2-KD), DHHC2-Overexpression (DHHC2-OE) and empty vector control (Ctrl) conditions via LC-MS/MS-based analysis. Our dataset revealed the identification of a total of 73 metabolites encompassing all the conditions, with only 22 showing significant differences in univariate analysis. Furthermore, we performed pathway analysis with metabolites having VIP ≥ 0.7, P value ≤ 0.05, and fold change (FC) > 2 in DHHC2-OE (upregulated) and FC < 0.5 in DHHC2-OE or FC > 2 in DHHC2-KD condition (downregulated). We unveiled significant expression of the pyrimidine metabolism, urea cycle, and aspartate metabolism due to the abundance of onco-metabolites such as glutamine, uridine, and glutamic acid in the DHHC2-KD condition. However, DHHC2 overexpression resulted in a higher expression of metabolites previously reported to be associated with anti-cancer activity, such as betaine and 5'-methylthioadenosine (5'-MTA). Overall, this study sheds light on the changes mediated by DHHC2 in a cancer cell metabolome and suggests avenues for further investigation into other DHHC isoforms and their metabolic aspects.
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Affiliation(s)
- Suchi Chaturvedi
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Madhya Pradesh 453552, India
| | - S Sibi Karthik
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Madhya Pradesh 453552, India
| | - Sushabhan Sadhukhan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala 678623, India; Physical & Chemical Biology Laboratory, Department of Biological Sciences and Engineering, Indian Institute of Technology Palakkad, Palakkad, Kerala, 678623, India.
| | - Avinash Sonawane
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Madhya Pradesh 453552, India.
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Chaturvedi S, Sonawane A. Recapitulating the potential contribution of protein S-palmitoylation in cancer. Cancer Metastasis Rev 2024; 44:20. [PMID: 39725785 DOI: 10.1007/s10555-024-10217-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/14/2024] [Indexed: 12/28/2024]
Abstract
Protein S-palmitoylation is a reversible form of protein lipidation in which the formation of a thioester bond occurs between a cysteine (Cys) residue of a protein and a 16-carbon fatty acid chain. This modification is catalyzed by a family of palmitoyl acyl transferases, the DHHC enzymes, so called because of their Asp-His-His-Cys (DHHC) catalytic motif. Deregulation of DHHC enzymes has been linked to various diseases, including cancer and infections. Cancer, a major cause of global mortality, is characterized by features like uncontrolled cell growth, resistance to cell death, angiogenesis, invasion, and metastasis. Several of these processes are controlled by DHHC-mediated S-palmitoylation of oncogenes or tumor suppressors, including growth factor receptors (e.g., EGFR), kinases (e.g., AKT), and transcription factors (e.g., β-catenin). Dynamic regulation of S-palmitoylation is also governed by protein depalmitoylases. These enzymes balance the cycling of palmitoylation and regulate cellular signaling, cell growth, and its organization. Given the significance of S-palmitoylation in cancer, the DHHCs and protein depalmitoylases are promising targets for cancer therapy. Here we summarize the catalytic mechanisms of DHHC enzymes and depalmitoylases, their role in cancer progression and prevention, as well as the crosstalk of palmitoylation with other post-translational modifications. Additionally, we discuss the methods to detect S-palmitoylation, the limitations of available DHHC-targeting inhibitors, and ongoing research efforts to address these obstacles.
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Affiliation(s)
- Suchi Chaturvedi
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, 453552, Simrol, Madhya Pradesh, India
| | - Avinash Sonawane
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, 453552, Simrol, Madhya Pradesh, India.
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3
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Kouba S, Demaurex N. S-acylation of Ca 2+ transport proteins in cancer. Chronic Dis Transl Med 2024; 10:263-280. [PMID: 39429488 PMCID: PMC11483607 DOI: 10.1002/cdt3.146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 10/22/2024] Open
Abstract
Alterations in cellular calcium (Ca2+) signals have been causally associated with the development and progression of human cancers. Cellular Ca2+ signals are generated by channels, pumps, and exchangers that move Ca2+ ions across membranes and are decoded by effector proteins in the cytosol or in organelles. S-acylation, the reversible addition of 16-carbon fatty acids to proteins, modulates the activity of Ca2+ transporters by altering their affinity for lipids, and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers. Here, we compile studies reporting an association between Ca2+ transporters or S-acylation enzymes with specific cancers, as well as studies reporting or predicting the S-acylation of Ca2+ transporters. We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca2+ transport proteins involved in cancer.
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Affiliation(s)
- Sana Kouba
- Department of Cell Physiology and MetabolismCentre Médical Universitaire, University of GenevaGenevaSwitzerland
| | - Nicolas Demaurex
- Department of Cell Physiology and MetabolismCentre Médical Universitaire, University of GenevaGenevaSwitzerland
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Wang C, Cui ZY, Chang HY, Wu CZ, Yu ZY, Wang XT, Liu YQ, Li CL, Du XG, Li JF. 2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein. Exp Biol Med (Maywood) 2023; 248:2393-2407. [PMID: 38159074 PMCID: PMC10903252 DOI: 10.1177/15353702231220671] [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: 08/18/2023] [Accepted: 10/16/2023] [Indexed: 01/03/2024] Open
Abstract
Palmitoylation, which is mediated by protein acyltransferase (PAT) and performs important biological functions, is the only reversible lipid modification in organism. To study the effect of protein palmitoylation on hypopharyngeal squamous cell carcinoma (HPSCC), the expression levels of 23 PATs in tumor tissues of 8 HPSCC patients were determined, and high mRNA and protein levels of DHHC9 and DHHC15 were found. Subsequently, we investigated the effect of 2-bromopalmitate (2BP), a small-molecular inhibitor of protein palmitoylation, on the behavior of Fadu cells in vitro (50 μM) and in nude mouse xenograft models (50 μmol/kg), and found that 2BP suppressed the proliferation, invasion, and migration of Fadu cells without increasing cell apoptosis. Mechanistically, the effect of 2BP on the transduction of BMP, Wnt, Shh, and FGF signaling pathways was tested with qRT-PCR, and its drug target was explored with western blotting and acyl-biotinyl exchange assay. Our results showed that 2BP inhibited the transduction of the FGF/ERK signaling pathway. The palmitoylation level of Ras protein decreased after 2BP treatment, and its distribution in the cell membrane structure was reduced significantly. The findings of this work reveal that protein palmitoylation mediated by DHHC9 and DHHC15 may play important roles in the occurrence and development of HPSCC. 2BP is able to inhibit the malignant biological behaviors of HPSCC cells, possibly via hindering the palmitoylation and membrane location of Ras protein, which might, in turn, offer a low-toxicity anti-cancer drug for targeting the treatment of HPSCC.
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Affiliation(s)
- Chen Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Zhao-Yang Cui
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Hai-Yan Chang
- Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Chang-Zhen Wu
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Zhao-Yan Yu
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Xiao-Ting Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Yi-Qing Liu
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Chang-Le Li
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Xiang-Ge Du
- Shandong Provincial Hospital, Shandong University, Jinan 250021, China
| | - Jian-Feng Li
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
- Institute of Eye and ENT, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
- Central Laboratory, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
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Shang S, Liu J, Hua F. Protein acylation: mechanisms, biological functions and therapeutic targets. Signal Transduct Target Ther 2022; 7:396. [PMID: 36577755 PMCID: PMC9797573 DOI: 10.1038/s41392-022-01245-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/27/2022] [Accepted: 11/06/2022] [Indexed: 12/30/2022] Open
Abstract
Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein-protein interactions and protein-DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.
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Affiliation(s)
- Shuang Shang
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
| | - Jing Liu
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
| | - Fang Hua
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
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Jia Z, Long D, Yu Y. Dynamic Expression of Palmitoylation Regulators across Human Organ Development and Cancers Based on Bioinformatics. Curr Issues Mol Biol 2022; 44:4472-4489. [PMID: 36286021 PMCID: PMC9600046 DOI: 10.3390/cimb44100306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/10/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Protein palmitoylation is a reversible modification process that links palmitate to cysteine residues via a reversible thioester bond. Palmitoylation exerts an important role in human organ development and tumor progression. However, a comprehensive landscape regarding the dynamic expression of palmitoylation regulators in human organ development remains unclear. In this study, we analyzed the dynamic expression of palmitoylation regulators in seven organ development and eight cancer types based on bioinformatics. We found that the expression levels of most palmitoylation regulators were altered after birth. In particular, ZDHHC7/20/21 exhibited converse expression patterns in multiple cancer types. Survival analysis showed that the poor prognosis in patients with kidney renal clear carcinoma (KIRC) is related to low expression of ZDHHC7/20/21, and a high expression of ZDHHC7/20/21 is related to worse survival in patients with liver hepatocellular carcinoma (LIHC). Furthermore, we found that the expression of ZDHHC7 is associated with infiltration levels of some types of immune cells in the tumor microenvironment (TME), and we explored the relationship between ZDHHC7 expression and immune checkpoint (ICP) genes across 33 cancer types. In addition, gene set enrichment analysis (GSEA) results indicated that ZDHHC7 might regulate different genes to mediate the same pathway in different organs. In summary, the comprehensive analysis of palmitoylation regulators reveals their functions in human organ development and cancer, which may provide new insights for developing new tumor markers.
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Affiliation(s)
- Zixian Jia
- College of Life Sciences, Northwest A&F University, Xianyang 712100, China
| | - Deyu Long
- College of Life Sciences, Northwest A&F University, Xianyang 712100, China
| | - Yingcui Yu
- College of Natural Resources and Environment, Northwest A&F University, Xianyang 712100, China
- Correspondence:
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Srivani Nagam L, Vadde R, Jinka R. Polymorphisms in hepatocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:125-133. [DOI: 10.1016/b978-0-323-98806-3.00013-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kitz J, Lefebvre C, Carlos J, Lowes LE, Allan AL. Reduced Zeb1 Expression in Prostate Cancer Cells Leads to an Aggressive Partial-EMT Phenotype Associated with Altered Global Methylation Patterns. Int J Mol Sci 2021; 22:ijms222312840. [PMID: 34884649 PMCID: PMC8657557 DOI: 10.3390/ijms222312840] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer is the most common cancer in American men and the second leading cause of cancer-related death. Most of these deaths are associated with metastasis, a process involving the epithelial-to-mesenchymal (EMT) transition. Furthermore, growing evidence suggests that partial-EMT (p-EMT) may lead to more aggressive disease than complete EMT. In this study, the EMT-inducing transcription factor Zeb1 was knocked down in mesenchymal PC-3 prostate cancer cells (Zeb1KD) and resulting changes in cellular phenotype were assessed using protein and RNA analysis, invasion and migration assays, cell morphology assays, and DNA methylation chip analysis. Inducible knockdown of Zeb1 resulted in a p-EMT phenotype including co-expression of epithelial and mesenchymal markers, a mixed epithelial/mesenchymal morphology, increased invasion and migration, and enhanced expression of p-EMT markers relative to PC-3 mesenchymal controls (p ≤ 0.05). Treatment of Zeb1KD cells with the global de-methylating drug 5-azacytidine (5-aza) mitigated the observed aggressive p-EMT phenotype (p ≤ 0.05). DNA methylation chip analysis revealed 10 potential targets for identifying and/or targeting aggressive p-EMT prostate cancer in the future. These findings provide a framework to enhance prognostic and/or therapeutic options for aggressive prostate cancer in the future by identifying new p-EMT biomarkers to classify patients with aggressive disease who may benefit from 5-aza treatment.
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Affiliation(s)
- Jenna Kitz
- London Regional Cancer Program, London Health Sciences Centre, Department of Anatomy & Cell Biology, Western University, London, ON N6A 5W9, Canada; (J.K.); (C.L.)
| | - Cory Lefebvre
- London Regional Cancer Program, London Health Sciences Centre, Department of Anatomy & Cell Biology, Western University, London, ON N6A 5W9, Canada; (J.K.); (C.L.)
| | - Joselia Carlos
- Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada;
| | - Lori E. Lowes
- Flow Cytometry, London Health Sciences Centre, London, ON N6A 5W9, Canada;
| | - Alison L. Allan
- London Regional Cancer Program, London Health Sciences Centre, Department of Anatomy & Cell Biology, Western University, London, ON N6A 5W9, Canada; (J.K.); (C.L.)
- Department of Oncology, Western University, London, ON N6A 5W9, Canada
- Cancer Research Laboratory Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
- Correspondence: ; Tel.: +1-519-685-8600 (ext. 55134)
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Chen JJ, Fan Y, Boehning D. Regulation of Dynamic Protein S-Acylation. Front Mol Biosci 2021; 8:656440. [PMID: 33981723 PMCID: PMC8107437 DOI: 10.3389/fmolb.2021.656440] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 02/16/2021] [Indexed: 12/20/2022] Open
Abstract
Protein S-acylation is the reversible addition of fatty acids to the cysteine residues of target proteins. It regulates multiple aspects of protein function, including the localization to membranes, intracellular trafficking, protein interactions, protein stability, and protein conformation. This process is regulated by palmitoyl acyltransferases that have the conserved amino acid sequence DHHC at their active site. Although they have conserved catalytic cores, DHHC enzymes vary in their protein substrate selection, lipid substrate preference, and regulatory mechanisms. Alterations in DHHC enzyme function are associated with many human diseases, including cancers and neurological conditions. The removal of fatty acids from acylated cysteine residues is catalyzed by acyl protein thioesterases. Notably, S-acylation is now known to be a highly dynamic process, and plays crucial roles in signaling transduction in various cell types. In this review, we will explore the recent findings on protein S-acylation, the enzymatic regulation of this process, and discuss examples of dynamic S-acylation.
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Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13061433. [PMID: 33801071 PMCID: PMC8004037 DOI: 10.3390/cancers13061433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in metastasis, but neither the mechanisms involved in this process nor the role of the different isoforms of the gene are known. Here we show that the ratio of these isoforms is related to the relapsing of the disease, and that the protein ZNF518B interacts with enzymes able to introduce epigenetic changes, which may affect the activity of many genes. We also report a list of genes affected in common by ZNF518B and by two of those related enzymes, namely, G9A and EZH2. An in-depth analysis of five of those genes revealed that ZNF518B is involved in the recruitment of the enzymes and in the deposition of the corresponding epigenetic marks. The results highlight the relevance of epigenetic changes in cancer development, and open the possibility of developing therapeutic approaches, as the introduction of epigenetic modifications is reversible. Abstract The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.
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Le X, Mu J, Peng W, Tang J, Xiang Q, Tian S, Feng Y, He S, Qiu Z, Ren G, Huang A, Lin Y, Tao Q, Xiang T. DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis. Theranostics 2020; 10:9495-9511. [PMID: 32863941 PMCID: PMC7449911 DOI: 10.7150/thno.45631] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer progression is an intricate biological process profiled by not only unscheduled proliferation, but also altered metabolism mechanisms. In this article, we introduced a novel tumor suppressor gene (TSG), Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as ZNF377), frequently silenced due to epigenetic modification among various cancers, which exerts significant anti-tumor effects through metabolic regulation. Methods: Quantitative reversed-transcription PCR (qRT-PCR), reverse transcription PCR (RT-PCR) and Western blot were employed to demonstrate transcriptional and protein levels of targeted regulators. Methylation of ZDHHC1 promoter was detected by bisulfite genomic sequencing (BGS) and methylation specific PCR (MSP). Proteomics were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) and gas chromatography-mass spectrometry (GC-MS) were utilized for metabolomics analysis. Cellular functions were examined via corresponding approaches. Nude mice were used for xenograft tumor models. Indirect immunofluorescence staining was utilized to obtain precise location and expression of target proteins. Oxidative and ER stress indicators were detected using specific kits. Results: We found that ZDHHC1 expression was frequently silenced in multiple tumor cells and specimens due to methylation. Restoration of ZDHHC1 expression can curb cancer cell progression via stimulating apoptosis and cell cycle arrest, repressing metastasis, and reversing EMT transition and cell stemness. ZDHHC1's salient anti-tumor abilities were recognized in vivo as well. Metabolomic and proteomic analyses predicted inhibitory role of ZDHHC1 in glucose metabolism pathways in a CYGB-dependent manner, and in pentose phosphate pathway (PPP), which was validated by examining altered key factors. Moreover, we unraveled that ZDHHC1 dedicates to the increment of oxidative stress and endoplasmic reticulum (ER) stress to promote pyroptosis for anticancer purposes. Conclusion: Our study for the first time indicates ZDHHC1 is a potential tumor-suppressor frequently silenced due to promoter methylation, capable of negatively regulating metabolisms of tumor cells while stimulating oxidative stress and ER stress to expedite cell death through induction of pyroptosis and apoptosis, which can be exploited for development of new cancer prevention and therapies.
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Affiliation(s)
- Xin Le
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junhao Mu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyan Peng
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Tang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shaorong Tian
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yixiao Feng
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Sanxiu He
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhu Qiu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ailong Huang
- MOE Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Disease, Chongqing Medical University, China
| | - Yong Lin
- Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA
| | - Qian Tao
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Tingxiu Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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12
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Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep 2018; 19:embr.201846666. [PMID: 30232163 DOI: 10.15252/embr.201846666] [Citation(s) in RCA: 251] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 07/24/2018] [Accepted: 08/16/2018] [Indexed: 12/11/2022] Open
Abstract
Protein S-palmitoylation is a reversible post-translational modification that alters the localization, stability, and function of hundreds of proteins in the cell. S-palmitoylation is essential for the function of both oncogenes (e.g., NRAS and EGFR) and tumor suppressors (e.g., SCRIB, melanocortin 1 receptor). In mammalian cells, the thioesterification of palmitate to internal cysteine residues is catalyzed by 23 Asp-His-His-Cys (DHHC)-family palmitoyl S-acyltransferases while the removal of palmitate is catalyzed by serine hydrolases, including acyl-protein thioesterases (APTs). These enzymes modulate the function of important oncogenes and tumor suppressors and often display altered expression patterns in cancer. Targeting S-palmitoylation or the enzymes responsible for palmitoylation dynamics may therefore represent a candidate therapeutic strategy for certain cancers.
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Affiliation(s)
- Pin-Joe Ko
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
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Wang S, Liu X, Huang J, Zhang Y, Sang C, Li T, Yuan J. Expression of KIAA1456 in lung cancer tissue and its effects on proliferation, migration and invasion of lung cancer cells. Oncol Lett 2018; 16:3791-3795. [PMID: 30127990 PMCID: PMC6096096 DOI: 10.3892/ol.2018.9119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 06/11/2018] [Indexed: 12/18/2022] Open
Abstract
The expression of human transfer ribonucleic acid (tRNA) methyltransferase 9-like (KIAA1456) protein in lung cancer tissue and its effects on certain genes involved in the proliferation, migration and invasion of lung cancer cells were investigated. Immunohistochemistry was applied to stain lung cancer tissue and adjacent tissue sections of 90 lung cancer patients, so as to evaluate the difference in the expression level of KIAA1456 between two tissues. The correlation of KIAA1456 expression with clinicopathological parameters of lung cancer was analyzed. Kaplan-Meier survival curves were used to analyze the relationship between KIAA1456 and postoperative survival in patients with lung cancer. KIAA1456 gene was overexpressed in lung cancer cell lines (A549 and GLC-15), and the influence of KIAA1456 gene on the expression of cyclin D1, neural cadherin (N-cadherin) and epithelial cadherin (E-cadherin) and their involvement in lung cancer cell proliferation, migration and invasion were observed. Compared with that in adjacent tissue, the expression of KIAA1456 in lung cancer tissue was significantly decreased (p<0.05). The low expression of KIAA1456 in lung cancer tissue was clearly associated with pathological tumor (pT) stage, pathological node (pN) stage, tumor-node-metastasis (TNM) stage and pathological stage, but had no correlation with sex, age, tumor size or histology of the patient. KIAA1456 low expression was related with poor prognosis of the lung cancer patient. According to Western blotting, the overexpression of KIAA1456 in lung cancer cells could inhibit the expressions of cyclin D1 and N-cadherin, and promote the expression of E-cadherin. The results show that KIAA1456 expression was low in lung cancer tissue, and was associated with poor prognosis in patients and was an independent prognostic factor in patients with lung cancer. Thus, KIAA1456 can be used as a tumor suppressor gene in lung cancer, suppressing the proliferation, migration and invasion of lung cancer cells.
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Affiliation(s)
- Shuling Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Department of Respiratory Medicine, The First People's Hospital of Xuzhou, Xuzhou, Jiangsu 221002, P.R. China
| | - Xiangqun Liu
- Department of Respiratory Medicine, The First People's Hospital of Xuzhou, Xuzhou, Jiangsu 221002, P.R. China
| | - Jianan Huang
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ying Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chunli Sang
- Department of Respiratory Medicine, The First People's Hospital of Xuzhou, Xuzhou, Jiangsu 221002, P.R. China
| | - Tao Li
- Department of Respiratory Medicine, The First People's Hospital of Xuzhou, Xuzhou, Jiangsu 221002, P.R. China
| | - Jieqing Yuan
- Department of Respiratory Medicine, The First People's Hospital of Xuzhou, Xuzhou, Jiangsu 221002, P.R. China
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14
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Zhang X, Zhang L, Ji G, Lei Q, Fang C, Lu H. Site-Specific Quantification of Protein Palmitoylation by Cysteine-Stable Isotope Metabolic Labeling. Anal Chem 2018; 90:10543-10550. [DOI: 10.1021/acs.analchem.8b02635] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Xiaoqin Zhang
- Shanghai Cancer Center, Fudan University, Shanghai 200032, People’s Republic of China
| | | | | | - Qunying Lei
- Shanghai Cancer Center, Fudan University, Shanghai 200032, People’s Republic of China
| | | | - Haojie Lu
- Shanghai Cancer Center, Fudan University, Shanghai 200032, People’s Republic of China
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15
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De I, Sadhukhan S. Emerging Roles of DHHC-mediated Protein S-palmitoylation in Physiological and Pathophysiological Context. Eur J Cell Biol 2018; 97:319-338. [DOI: 10.1016/j.ejcb.2018.03.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/14/2018] [Accepted: 03/16/2018] [Indexed: 02/08/2023] Open
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16
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Flentje A, Kober KM, Carrico AW, Neilands TB, Flowers E, Heck NC, Aouizerat BE. Minority stress and leukocyte gene expression in sexual minority men living with treated HIV infection. Brain Behav Immun 2018; 70:335-345. [PMID: 29548994 PMCID: PMC5953835 DOI: 10.1016/j.bbi.2018.03.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/20/2018] [Accepted: 03/12/2018] [Indexed: 12/17/2022] Open
Abstract
Sexual minority (i.e., non-heterosexual) individuals experience poorer mental and physical health, accounted for in part by the additional burden of sexual minority stress occurring from being situated in a culture favoring heteronormativity. Informed by previous research, the purpose of this study was to identify the relationship between sexual minority stress and leukocyte gene expression related to inflammation, cancer, immune function, and cardiovascular function. Sexual minority men living with HIV who were on anti-retroviral medication, had viral load < 200 copies/mL, and had biologically confirmed, recent methamphetamine use completed minority stress measures and submitted blood samples for RNA sequencing on leukocytes. Differential gene expression and pathway analyses were conducted comparing those with clinically elevated minority stress (n = 18) and those who did not meet the clinical cutoff (n = 20), covarying reactive urine toxicology results for very recent stimulant use. In total, 90 differentially expressed genes and 138 gene set pathways evidencing 2-directional perturbation were observed at false discovery rate (FDR) < 0.10. Of these, 41 of the differentially expressed genes and 35 of the 2-directionally perturbed pathways were identified as functionally related to hypothesized mechanisms of inflammation, cancer, immune function, and cardiovascular function. The neuroactive-ligand receptor pathway (implicated in cancer development) was identified using signaling pathway impact analysis. Our results suggest several potential biological pathways for future work investigating the relationship between sexual minority stress and health.
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Affiliation(s)
- Annesa Flentje
- Community Health Systems, School of Nursing, University of California, San Francisco, United States.
| | - Kord M Kober
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, United States; Institute for Computational Health Sciences, University of California, San Francisco, United States
| | | | - Torsten B Neilands
- Center for AIDS Prevention Studies, Department of Medicine, University of California, San Francisco, United States
| | - Elena Flowers
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, United States
| | - Nicholas C Heck
- Department of Psychology, Marquette University, United States
| | - Bradley E Aouizerat
- Bluestone Center for Clinical Research, College of Dentistry, New York University, United States
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17
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Peng C, Hu W, Weng X, Tong R, Cheng S, Ding C, Xiao H, Lv Z, Xie H, Zhou L, Wu J, Zheng S. Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8. Sci Rep 2017; 7:4186. [PMID: 28646235 PMCID: PMC5482898 DOI: 10.1038/s41598-017-04045-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 05/16/2017] [Indexed: 02/08/2023] Open
Abstract
It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target.
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Affiliation(s)
- Chuanhui Peng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Wendi Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Xiaoyu Weng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Rongliang Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Shaobing Cheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Chaofeng Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Heng Xiao
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhen Lv
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.
- Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
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18
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Liu S, Kawamoto T, Morita O, Yoshinari K, Honda H. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models. Toxicol Appl Pharmacol 2017; 318:79-87. [PMID: 28108177 DOI: 10.1016/j.taap.2017.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 10/20/2022]
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19
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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20
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Chen XP, Luo JS, Tian Y, Nie CL, Cui W, Zhang WD. Downregulation of Heparanase Expression Results in Suppression of Invasion, Migration, and Adhesion Abilities of Hepatocellular Carcinoma Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:241983. [PMID: 26839882 PMCID: PMC4709605 DOI: 10.1155/2015/241983] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/31/2015] [Accepted: 11/03/2015] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Heparanase (HPSE) is high-expressed in most malignant tumors including hepatocellular carcinoma (HCC) and promotes cancer cell invasion and migration. The aim of the study is to explore whether HPSE enhances adhesion in metastasis of HCC cells. METHODS HPSE expressions in human HCC cells were measured with real-time RT-PCR and Western blot analysis. Four recombinant miRNA vectors pcDNATM6.2-GW/EmGFP-miR-HPSE (pmiR-HPSE) were transfected into HCCLM3 cell. HPSE expression in transfected cell was measured. The cell invasion, migration, and adhesion abilities were detected, respectively. RESULTS Both HPSE mRNA and protein relative expression levels were higher in HepG2, BEL-7402, and HCCLM3 cells than those in normal hepatocyte (P < 0.05). HPSE showed highest expression level in HCCLM3 cell (P < 0.05). Transfection efficiencies of four miRNA vectors were 75%-85%. The recombinant vectors significantly decreased HPSE expression in transfected HCCLM3 cells (P < 0.01), and pmiR-HPSE-1 showed best interference effect (P < 0.05). pmiR-HPSE-1 significantly decreased the penetrated and migrating cells numbers and adherence rate of HCCLM3 cells (P < 0.05). CONCLUSION HPSE is a potentiator of cell adhesion in metastasis of HCC.
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Affiliation(s)
- Xiao-Peng Chen
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
| | - Jun-Sheng Luo
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
| | - Ye Tian
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
| | - Chen-Lin Nie
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
| | - Wei Cui
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
| | - Wei-Dong Zhang
- Department of Hepatobiliary Surgery, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu 241001, China
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21
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Protein S-palmitoylation and cancer. Biochim Biophys Acta Rev Cancer 2015; 1856:107-20. [PMID: 26112306 DOI: 10.1016/j.bbcan.2015.06.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/16/2015] [Accepted: 06/21/2015] [Indexed: 12/16/2022]
Abstract
Protein S-palmitoylation is a reversible posttranslational modification of proteins with fatty acids, an enzymatic process driven by a recently discovered family of protein acyltransferases (PATs) that are defined by a conserved catalytic domain characterized by a DHHC sequence motif. Protein S-palmitoylation has a prominent role in regulating protein location, trafficking and function. Recent studies of DHHC PATs and their functional effects have demonstrated that their dysregulation is associated with human diseases, including schizophrenia, X-linked mental retardation, and Huntington's Disease. A growing number of reports indicate an important role for DHHC proteins and their substrates in tumorigenesis. Whereas DHHC PATs comprise a family of 23 enzymes in humans, a smaller number of enzymes that remove palmitate have been identified and characterized as potential therapeutic targets. Here we review current knowledge of the enzymes that mediate reversible palmitoylation and their cancer-associated substrates and discuss potential therapeutic applications.
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22
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Jiang YX, Du ZM, Jiao L, Shao Q, Fu S, Shao JY, Zhu XF, Ernberg I, Li YH. Inhibition of MiR-155 suppresses cell migration in nasopharyngeal carcinoma through targeting ZDHHC2. Int J Clin Exp Med 2015; 8:8472-8484. [PMID: 26309499 PMCID: PMC4538107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 05/31/2015] [Indexed: 06/04/2023]
Abstract
Overexpression of miR-155 in nasopharygeal carcinoma (NPC) is partly driven by Epstein-Bar virus infection. However the role of miR-155 in NPC oncogenesis is unclear. This study showed that miR-155 inhibitor could inhibit the cell migration in NPC cell lines. ZDHHC2 was identified as a direct target of miR-155 and downregulation of ZDHHC2 prompted cell migration in NPC. Furthermore, reduced ZDHHC2 expression was associated significantly with metastasis and poor survival of NPC patients. Collectively, inhibition of miR-155 suppresses cell migration in NPC through targeting ZDHHC2. The potential of miR-155 and ZDHHC2 as therapeutic targets in NPC should be further investigated.
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Affiliation(s)
- Yuan-Xue Jiang
- Sate key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Zi-Ming Du
- Sate Key Laboratory of Oncology in South China, Department of Pathology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Lin Jiao
- Sate Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Qiong Shao
- Sate Key Laboratory of Oncology in South China, Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Sha Fu
- Sate Key Laboratory of Oncology in South China, Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Jian-Yong Shao
- Sate Key Laboratory of Oncology in South China, Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Xiao-Feng Zhu
- Sate Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
| | - Ingemar Ernberg
- Department of Microbiolgy, Tumor and Cell Biology, Karolinska InstitutetStockholm, Sweden
| | - Yu-Hong Li
- Sate key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhou, P.R. China
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