title: Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells.
abstract: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.
authors.affiliation: Departments of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Digestive diseases, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: The Hong Kong Polytechnic University Shenzhen Research Institute, Hong Kong, China ; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Ben C B
authors.initials: BC
authors.lastname: Ko
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006657:Histones / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000191:economics* / Q000235:genetics; D019098:Telomerase / Q000235:genetics*
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D019098:Telomerase; D056564:Sirtuin 1