TRIM29 promotes hepatocellular carcinoma progression by inducing K48-linked ubiquitination and degradation of DAPK3

Abstract Tripartite motif 29 (TRIM29) is a member of the subfamily of the E3 ubiquitin ligases and regulates several cellular processes in cancer. However, the role of TRIM29 in hepatocellular carcinoma (HCC) and the underlying mechanism remain undetermined. In this study, we discovered that TRIM29 was upregulated in human HCC compared with normal specimens and correlated with poor survival for HCC patients. Functionally, TRIM29 was found to act as an oncogene, which enhances proliferation and inhibits apoptosis of HCC cell line MHCC97H and Hep3B. Mechanistically, TRIM29 directly interacts with DAPK3 and promotes the K48-linked ubiquitination and proteasomal degradation through the K261 Lysine site of DAPK3. The reduction in cell survival and increase in apoptosis caused by TRIM29 depletion can be reversed by co-downregulation of DAPK3. Moreover, TRIM29 negatively regulates apoptotic response induced by sorafenib treatments, with its depletion promoting drug sensitization. Overall, these findings indicate that TRIM29 promotes proliferation and inhibits apoptosis via ubiquitination-mediated degradation of DAPK3 in HCC, which provides a promising therapeutic target and a biomarker for prognosis.