LAUSR

Abstract Background SIRT6 belongs to class III sirtuin family with NAD+ -dependent histone deacetylase activities and controls multiple processes including aging, metabolism and inflammation. In recent years, increasing studies showed tumor suppressor role of SIRT6 in HCC development. Methods We established a two-stage DEN followed CCl4 induced liver carcinogenesis in the hepatic-specific SIRT6 HKO mice models. The HCC cells were transfected with SIRT6 shRNA or pcDNA3.1-SIRT6 for knockdown or overexpression of SIRT6. The tumor formation was examined by the xenograft mice experiments. Results We found that hepatic SIRT6 deficit significantly promotes liver injury and liver cancer through inhibition of the ERK1/2 pathway. SIRT6 was compensatory upregulated in mice tumor tissues and human HCC cells and overexpressed SIRT6 inhibits tumor growth both in vitro and in vivo. Conclusions Taken together, we provide a useful mouse model for delineating the molecular pathways involved in chronic liver diseases and primary liver cancer and suggest that SIRT6 can be a promising target for HCC therapies.