The RBPJ/DAPK3/UBE3A signaling axis induces PBRM1 degradation to modulate the sensitivity of renal cell carcinoma to CDK4/6 inhibitors.

Renal cell carcinoma (RCC) is a kind of malignant tumor originating from the renal tubular epithelium. Approximately 30% of patients with renal cancer are found to have metastasis when first diagnosed. Exploring other effective treatment methods in addition to surgery is an urgent need in the research field of renal cell carcinoma. Polybromo 1 (PBRM1) is the second most mutated gene in RCC, with a mutation rate of ~40%. Notably, the posttranscriptional modification of PBRM1 in RCC is unclear. In this study, we performed unbiased mass spectrometry of PBRM1 and identified ubiquitin-protein ligase E3A (UBE3A), an extensively studied E3 ligase that can bind with PBRM1 and regulate the stability of PBRM1 in renal cancer cells. We further found that RBPJ/DAPK3 modulated the E3 ligase activity of UBE3A by interfering with the PKA phosphorylation of UBE3A. Finally, we demonstrated that the RBPJ/DAPK3/UBE3A/PBRM1/p21 axis contributed to the sensitivity of renal cancer cells to CDK4/6 inhibitors. In addition, in combination with RBPJ inhibitors, CDK4/6 inhibitors showed synergistically enhanced effects on renal cancer cells. In summary, we not only revealed a novel RBPJ/DAPK3/UBE3A/PBRM1/p21 signaling axis but also identified a combination strategy for overcoming the resistance of renal cancer cells to CDK4/6 inhibitors.