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

Abstract

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.

PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer

“…PBRM1 has been involved in anti-tumor effects of immune checkpoint therapy 32 and inhibitors against ATR (Ataxia telangiectasia mutated and Rad3-related), 19 , 33 PARP, 19 , 33 EZH2 (enhancer of zeste homolog 2), 34 and CDK (cyclin dependent kinases). 35 Our findings linked PBRM1 to cisplatin, paclitaxel, and olaparib, widening our understanding of this gene regarding its role in anti-tumor therapy. Cisplatin is a prototypical platinum-based chemotherapeutic agent, while carboplatin is a derivative of cisplatin.…”

Loss ofUBE3Aimpacts both neuronal and non-neuronal cells in human cerebral organoids

“…Furthermore, many corticogenesis-and neurogenesis-related pathways including RHO GTPase cycle 38 , estrogen receptor signaling 39 , docosahexaenoic acid (DHA) signaling 40 , EPH-Ephrin signaling 41 , mTOR signaling 42 , reelin signaling in neurons 43 , intra-golgi and retrograde golgi to ER traffic 44 , and signaling by ROBO receptors 45 were affected by the absence of UBE3A (Figure 2D and Table S1). Many cancer-and cardiac-related pathways were also deregulated by the absence of UBE3A (Table S1) which is not surprising due to UBE3A's potential role in these pathways/mechanisms 46,47 . However, within the scope of the cerebral organoid model, we focused mainly on pathways related to neurodevelopment.…”

Tumor-associated macrophage-derived exosomes LINC01592 induce the immune escape of esophageal cancer by decreasing MHC-I surface expression

“…In accordance with prior documented procedures, Co-IP assays were performed [ 16 , 29 – 31 ]. A detailed description of the antibodies used can be found in Table S4.…”