Identification of UBE3C as an E3 ubiquitin ligase for mutant BRAF.

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations have been implicated in a variety of cancer types, with the BRAF V600E (BRAF) mutation being particularly prevalent and recognized as a significant therapeutic target. BRAF inhibitors, such as Vemurafenib, represent a targeted therapeutic option for patients harboring this mutation. While these treatments often elicit a substantial initial response, they are frequently followed by the rapid development of resistance, which is mediated by various regulatory mechanisms. As a result, the pathways governing the BRAF remain poorly understood, thereby complicating strategies to counteract resistance. In the current study, we employed a tandem affinity purification approach to demonstrate that UBE3C interacts with BRAF. Our findings indicate that UBE3C binds to the kinase domain of BRAF and facilitates its ubiquitination. We further assessed the clinical significance of both BRAF and UBE3C across various models. Additionally, we established that the stability of BRAF is contingent upon the activity of heat shock protein 90 (HSP90) and is modulated by UBE3C expression. These results suggest that targeting UBE3C may provide a novel strategy to overcome secondary resistance to the BRAF inhibitor Vemurafenib. Our findings indicate that UBE3C plays a critical role in tumor biology and may offer a new avenue for managing acquired resistance in patients with BRAF-mutant cancers.