title: Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.
abstract: Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT [corrected] in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.
authors.affiliation: The State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.forename: Anthony W I
authors.initials: AW
authors.lastname: Lo
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.forename: Margaret H L
authors.initials: MH
authors.lastname: Ng
authors.forename: Cecilia Y S
authors.initials: CY
authors.lastname: Ho
authors.forename: Suk-Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
authors.forename: Ai-Long
authors.initials: AL
authors.lastname: Huang
authors.forename: Xue-Fei
authors.initials: XF
authors.lastname: Cai
authors.forename: Ben C B
authors.initials: BC
authors.lastname: Ko
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D000089804:Shelterin Complex; D056564:Sirtuin 1 / Q000032:analysis / Q000502:physiology*; D019098:Telomerase / Q000032:analysis / Q000502:physiology; D016615:Telomere; D034501:Telomere-Binding Proteins / Q000032:analysis / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation
chemical_list: C495876:ACD protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C509186:TERT protein, human; D019098:Telomerase; C447939:SIRT1 protein, human; D056564:Sirtuin 1