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. We established a two-stage DEN followed CCl4 induced liver carcinogenesis in the hepatic-specific SIRT6 HKO mice models and 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. 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.

SIRT6 属于 III 类 sirtuin 家族，具有 NAD+ 依赖性组蛋白脱乙酰酶活性，并控制包括衰老、新陈代谢和炎症在内的多个过程。近年来，越来越多的研究表明 SIRT6 在 HCC 发展中的抑癌作用。我们在肝脏特异性 SIRT6 HKO 小鼠模型中建立了 CCl4 诱导的肝癌发生的两阶段 DEN，发现肝脏 SIRT6 缺陷通过抑制 ERK1/2 通路显着促进肝损伤和肝癌。SIRT6 在小鼠肿瘤组织和人 HCC 细胞中补偿性上调，过表达的 SIRT6在体外和体内均抑制肿瘤生长. 总之，我们提供了一个有用的小鼠模型来描述慢性肝病和原发性肝癌的分子通路，并表明 SIRT6 可以成为 HCC 治疗的有希望的靶点。