Sirtuin6 (SIRT6) Promotes the EMT of Hepatocellular Carcinoma by Stimulating Autophagic Degradation of E-Cadherin.

EMT is a pivotal mechanism involved in tumor metastasis, which is the leading cause of poor prognosis for hepatocellular carcinoma (HCC). Sirtuin family members function as NAD+-dependent deacetylases that are essential for tumor metastasis and epithelial-mesenchymal transition (EMT). However, no causal association has been established between Sirtuin6 (SIRT6) and HCC metastasis. SIRT6 expression pattern and its association with HCC metastasis were investigated by informatic analysis, and verified by qRT-PCR and immunochemistry in HCC tissues. Transwell assay, qRT-PCR, and immunofluorescence assay were utilized to assess the effects of SIRT6 on metastasis and E-cadherin expression in vitro and in vivo. Immunoprecipitation assay was performed to observe whether SIRT6 deacetylated Beclin-1 in HCC cells. Immunofluorescence assay and inhibitor treatment rescue experiments were used to clarify the mechanism by which SIRT6 facilitated EMT and metastasis. SIRT6 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival, disease-relapse free survival, and HCC metastasis. Furthermore, SIRT6 promoted HCC cell migration, invasion, and EMT. Mechanistically, we found that SIRT6 deacetylated Beclin-1 in HCC cells and this event led to the promotion of the autophagic degradation of E-cadherin. Noticeably, E-cadherin degradation and invasion, migration induced by SIRT6 overexpression could be rescued by dual mutation of Beclin-1 (inhibition of acetylation), CQ (autophagy inhibitor), and knockdown of Atg7. In addition, SIRT6 promoted N-cadherin and Vimentin expression via deacetylating FOXO3a in HCC. These results established a relationship between SIRT6 and HCC EMT and further elucidated the mechanisms underlying HCC metastasis, helping provide a promising approach for the treatment of HCC. IMPLICATIONS: Inhibiting SIRT6 represents a potential therapeutic approach to suppress HCC metastasis partially through reduction of autophagic degradation of E-cadherin. ©2019 American Association for Cancer Research.