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^V600E) 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^V600E 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^V600E. Our findings indicate that UBE3C binds to the kinase domain of BRAF^V600E and facilitates its ubiquitination. We further assessed the clinical significance of both BRAF^V600E and UBE3C across various models. Additionally, we established that the stability of BRAF^V600E 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.