Zhu, Chenxuan2025-09-112025-09-112025-09-11http://hdl.handle.net/10393/50850https://doi.org/10.20381/ruor-31384Renal cell carcinoma (RCC) arises from the proximal tubules of the kidney. A hallmark of RCC is the frequent inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL functions as a substrate recognition component of an E3 ubiquitin ligase complex, targeting proteins for proteasomal degradation. The best-characterized substrate of VHL is the hypoxia-inducible factor (HIF). VHL loss in clear cell RCC (ccRCC) leads to HIF stabilization, activating gene transcription programs associated with tumorigenesis. This thesis investigates a novel, HIF-independent function of VHL in ccRCC oncogenesis. Based on our previous study that identified pRb as a novel VHL target, I validated the VHL-pRb interaction in ccRCC cells by co-immunoprecipitation (CO-IP). I demonstrated that pRb hyperaccumulation contributes to the oncogenic phenotype of VHL-deficient ccRCC cells. To characterize this pathway, I employed a proximity-labeling technique split-TurboID and identified an important downstream regulator of VHL-pRb pathway, canonical BAF (CBAF) chromatin remodeling complex. I next confirmed that the interaction between pRb and the core CBAF subunit ARID1A depends on VHL, revealing a previously unrecognized link between VHL, pRb, and chromatin remodeling machinery. Although the E3 ligase responsible for VHL-mediated pRb destabilization remains unidentified, I uncovered a potential link between the VHL-pRb axis and the stress granules, opening a new avenue for future investigation. Overall, in this study I will characterize a novel VHL-pRb-CBAF pathway, expanding the role of VHL beyond HIF regulation and providing mechanistic insights into ccRCC oncogenesis. This pathway represents a promising area for future investigation and a potential therapeutic vulnerability in VHL-deficient cancers.enKidney cancerClear cell renal cell carcinomaVHL diseaseHIF-independent role of VHLVHL regulation of pRbccRCC pathogenesisChromatin remodeling complexCanonical BAF and pRbStress granuledysregulated pathways in ccRCCThesis