aCBLC-mediated ubiquitin transfer from UBE2L6 to p53 accelerates ovarian cancer development

To identify potential biomarkers implicated in ovarian cancer (OV) progression, we first conducted mRNA-sequencing to analyze gene expression profiles in OV and normal tissues. Among the differentially expressed genes, the E3 ubiquitin ligase CBL Proto-Oncogene C (CBLC) with a significant up-regulation in OV tissues (log 2 FC = 9.56, adj. P < 0.001) drew our attention. This elevated expression of CBLC was further validated in a cohort of OV ( n = 27) and normal ( n = 30) tissues. Clinically, a higher proportion of p53 wild-type patients with elevated CBLC expression were diagnosed at stage III or IV compared to those in the low CBLC expression group. Functional assays demonstrated that down-regulation of CBLC suppressed proliferation and metastasis, while promoting apoptosis both in vivo and in vitro . Conversely, CBLC overexpression exerted tumor-promoting effects. Mechanistically, we identified the tumor suppressor p53 as an interacting partner of CBLC. CBLC promoted ubiquitin-mediated degradation of p53, and this process was facilitated by the E2 ligase UBE2L6, known to transfer ubiquitin to the substrates through the E3 ubiquitin ligase, which was also found to interact with CBLC. Overexpression of UBE2L6 enhanced p53 ubiquitination, an effect that was abolished upon CBLC knockdown. Furthermore, p53 overexpression attenuated the proliferative and invasive capacities of CBLC-overexpressing TOV21G cells. In summary, our findings indicate that the CBLC-UBE2L6 axis promotes OV progression by driving ubiquitination-dependent degradation of p53, highlighting its potential as a therapeutic target in OV.