An NAD+-Dependent Deacetylase SIRT7 Promotes HCC Development Through Deacetylation of USP39

Ubiquitin specific protease 39 (USP39), an ortholog of Sad1p in yeast, is essential for spliceosome assembly during pre-mRNA splicing in human. Although it is known that USP39 is upregulated and plays an oncogenic role in hepatocellular carcinoma (HCC), the underlying mechanism remains unknown. The results of this study demonstrated that USP39 can be acetylated by the histone acetyltrans-ferase MYST1, which is required for its proteasome-mediated degradation by Von Hippel-Lindau protein. In HCC cells, USP39 interacts with and is deacetylated by the lysine deacetylase sirtuin 7 (SIRT7). Notably, the deacetylation of USP39 by SIRT7 promotes its stability and thereby accelerates HCC cell proliferation and tumorigenesis in vitro and in vivo. Our data demonstrated a novel mechanism by which SIRT7 modulates the deacetylation of USP39 to promote HCC develop-ment, thus providing an effective anti-tumor therapeutic strategy for HCC.