Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth

Juan Chen, Bin Zhang, Nathalie Wong, Anthony W.I. Lo, Ka Fai To, Anthony W.H. Chan, Margaret H.L. Ng, Cecilia Y.S. Ho, Suk Hang Cheng, Paul B.S. Lai, Jun Yu, Ho Keung Ng, Ming Tat Ling, Ai Long Huang, Xue Fei Cai, Chi Bun Ko

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142 Citations (Scopus)

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 shelterin 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 PTOP 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.
Original languageEnglish
Pages (from-to)4138-4149
Number of pages12
JournalCancer Research
Volume71
Issue number12
DOIs
Publication statusPublished - 15 Jun 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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