TRIM11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome mediated degradation of PHLPP1.

Background & aims Hepatocellular carcinoma (HCC) is one of the main types of primary liver cancer with high morbidity and mortality, and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC have not been elucidated. Approach & results Through clinical analysis, we found that the expression of TRIM11 was upregulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with PH domain leucine rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1, thus promoted activation of protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. Conclusions Our study confirmed that TRIM11 plays an oncogenic role in hepatocellular carcinoma through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of hepatocellular carcinoma.