Loss of SIRT6 in hepatocellular carcinomas: associated molecular traits and clinical implications

Abstract

Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD-dependent deacetylases. It is involved in epigenetic regulation of many cellular processes such as DNA repair, fat metabolism, glucose homeostasis and aging by interacting with key molecules and signaling pathways such as NF-kB and HIF1A. Loss of SIRT6 results in uncontrolled glycolysis, triglyceride synthesis, and increased oxidative stress ultimately leading to hepatic steatosis. The role of SIRT6 in hepatocarcinogenesis remains to be elucidated.SIRT6 expression was investigated in primary human liver cancers, normal and cirrhotic livers using gene expression and tissue microarrays. A SIRT6 knock out (KO) gene expression signature was generated from hepatoctyes isolated from SIRT6 deficient animals using gene expression microarrays. Progressive downregulation of SIRT6 was observed in both cirrhotic livers and primary human HCC. Genetic loss of SIRT6 resulted in de-regulation of key signaling pathways such as NF-kB and disruption of cell cycle regulation. Consistently, downregulation of genes important for metabolism, differentiation and redox homeostasis was observed. Moreover, the generated SIRT6-KO signature clustered primary HCC patients in two main subgroups associated with the overall outcome of HCC patients. A significant shortened mean survival time and increased tumor recurrence was associated with inhibition of SIRT6 signaling. Further, disrupted SIRT6 signaling was observed in patients with poorly differentiated tumors with high AFP levels and metastatic disease. Finally, we could demonstrate that the generated SIRT6-KO signature possessed a predictive value for tumors other than HCC, i.e. breast and lung cancer. In conclusion, downregulation of SIRT6 and genes embedded in SIRT6 signaling has an oncogenic effect in hepatocarcinogenesis. Further, we here demonstrate the importance of intact SIRT6 signaling for the outcome of HCC and other cancer patients.