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 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.

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

“…Although SIRT1 expression is purposed to prevent HCC in this model, we observed a strong overexpression of SIRT1 in human HCC tumors and HCC cell lines. This observation confirms other studies that have documented SIRT1 overexpression in panels of human HCC samples (28)(29)(30). In cancer research, there are more examples emerging of how malignant cells have the ability to hijack survival mechanisms used by nonmalignant cells for their own endurance (31,32).…”

DBC1 does not function as a negative regulator of SIRT1 in liver cancer

“…Many studies have shown that SIRT1 levels are significantly elevated in prostate cancer, ovarian cancer, gastric cancer, colorectal cancer and hepatocellular carcinoma (13)(14)(15)(16)(17). Moreover, SIRT1 inhibition has been reported to suppress cell growth and induce cell cycle arrest or apoptosis in cancer cells (13)(14)(15)(16)(17).…”

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…On the other hand, it was also reported that in age-related cataracts in healthy older humans there was a lower level of SIRT1 expression, and the levels of SIRT1, p53, FOXO3, and FOXO4 were comparable to data from young subjects [120]. It is also clear that the antiapoptotic role of SIRT1 can contribute to increased tumor growth [121], which can be attenuated by SIRT1 inhibitors. The complexity of SIRT1 in senescence involves stem cell differentiation, which emphasizes the role of SIRT1 in controversial processes during aging [122].…”