The E3 ubiquitin ligase MG53 inhibits hepatocellular carcinoma by targeting RAC1 signaling.

Ras-related C3 botulinum toxin substrate 1 (RAC1) overexpressiosn and hyperactivation are correlated with aggressive growth and other malignant characteristics in a wide variety of cancers including hepatocellular carcinoma (HCC). However, the regulatory mechanism of RAC1 expression and activation in HCC is not fully understood. Here, we demonstrated that E3 ubiquitin ligase MG53 (also known as tripartite motif 72, TRIM72) acted as a direct inhibitor of RAC1, and it catalyzed the ubiquitination of RAC1 and further inhibited RAC1 activity in HCC cells. Mechanistically, MG53 directly bound with RAC1 through its coiled-coil domain and suppressed RAC1 activity by catalyzing the Lys48 (K48)-linked polyubiquitination of RAC1 at Lys5 residue in HCC cells. We further demonstrated that MG53 significantly suppressed the malignant behaviors of HCC cells and enhanced the chemosensitivity of HCC cells to sorafenib treatment by inhibiting RAC1-MAPK signaling axis. In summary, we identified MG53 as a novel RAC1 inhibitor and tumor suppressor in HCC, and it suppressed HCC progression by inducing K48-linked polyubiquitination of RAC1 and further inhibiting the RAC1-MAPK signaling. Altogether, our investigation provided a new therapeutic strategy for RAC1 overactivated tumors by modulating MG53.