Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients
Open Access
- 23 March 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 58 (3), 1054-1064
- https://doi.org/10.1002/hep.26413
Abstract
Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+–dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down‐regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3‐week‐old Sirt6‐deficient animals. Sirt6‐deficient hepatocytes showed up‐regulation of established hepatocellular carcinoma (HCC) biomarkers alpha‐fetoprotein (Afp), insulin‐like growth factor 2 (Igf2), H19, and glypican‐3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis‐insensitive. Re‐expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95‐stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte‐specific Sirt6‐KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6‐KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer). Conclusion: Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down‐regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients. (Hepatology 2013;53:1054–1064)Keywords
This publication has 40 references indexed in Scilit:
- Distribution of 5-Hydroxymethylcytosine in Different Human TissuesJournal of Nucleic Acids, 2011
- When Sirtuins and NF-κB CollideCell, 2009
- Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysisHepatology, 2008
- SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatinNature, 2008
- Comparative and integrative functional genomics of HCCOncogene, 2006
- Dysregulation of growth factor signaling in human hepatocellular carcinomaOncogene, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Targeting multidrug resistance in cancerNature Reviews Drug Discovery, 2006
- Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6Cell, 2006
- The history of cancer epigeneticsNature Reviews Cancer, 2004