Tumor necrosis factor receptor‐associated factor 6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation

Tumor necrosis factor receptor‐associated factor 6 (TRAF6) has been found to be involved in carcinogenesis in multiple cancers. However, the precise role of TRAF6 in cancer has not been extensively investigated and remains largely unknown. In this study, we aimed to investigate the biological function of TRAF6 and its underlying molecular mechanisms in cancer. A positive correlation between poor tumor differentiation and TRAF6 expression status was observed in both oral cancer and breast cancer. Overexpression of TRAF6 promoted proliferation, migration, and G0/G1 to S phase transition in tumor cells. Tumor necrosis factor receptor‐associated factor 6‐mediated AKT ubiquitination and subsequent phosphorylation played an essential role in the control of tumor cell malignant behavior. In vivo treatment with TRAF6, but not the E3 ligase deficient TRAF6 mutant, facilitated tumor growth. Our findings indicate that TRAF6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation. Therefore, TRAF6 could serve as a therapeutic target in cancers. Tumor necrosis factor receptor‐associated factor 6 (TRAF6) has been suggested as an oncogene in various human cancer types. However, the mechanism by which TRAF6 contributes to cancer development and progression is not clear. In the present study, we show that TRAF6‐mediated AKT ubiquitination and phosphorylation play important roles during the malignant progression of tumors. Our study also provides evidence that TRAF6 could be a potential therapeutic target in cancer.