Hypoxia-mediated high expression of TRIM15 promotes malignant progression of high-grade serous ovarian cancer through activation of AKT signaling pathway by K63 ubiquitination

The tripartite motif (TRIM) family member TRIM15 is an E3 ubiquitin ligase that is abnormally expressed in a variety of tumors, but its role and mechanism in high-grade serous ovarian cancer (HGSOC) are unclear. Here, we found for the first time that TRIM15 was upregulated in HGSOC and was associated with poor overall survival. Functional experiments showed that TRIM15 drove the proliferation of HGSOC cells and inhibited the apoptosis of tumor cells in vivo and in vitro. In terms of mechanism, we found that TRIM15 contributed to the malignant proliferation of HGSOC cells by promoting the activation of AKT and that there was a direct binding between them. TRIM15 induced lysine-63 (K63) ubiquitination of AKT through its Ring domain, which in turn activated the AKT signaling pathway. In addition, TRIM15-mediated K63 ubiquitination occurs mainly in the pleckstrin homology (PH) domain of AKT. We further identified other proteins and their functions regulated by TRIM15 in HGSOC cells by ubiquitin proteomic analysis. Furthermore, hypoxia-inducible factor-1α promoted TRIM15 transcriptional activation by binding to the hypoxia response elements of the TRIM15 promoter. Our study suggests that TRIM15 induces K63 ubiquitination of the AKT PH domain through its Ring domain and activates the AKT signaling pathway, thereby promoting HGSOC progression. In addition, the abnormally high expression of TRIM15 was associated with the hypoxic microenvironment of HGSOC tissues.