Metastatic clear cell renal cell carcinoma (ccRCC) has low disease-free survival and limited therapeutic options. The only treatments for ccRCC have been elucidated as a result of mechanistic understanding of tumor suppression by VHL (von Hippel-Lindau), the most commonly mutated gene in ccRCC. After VHL, the second most commonly mutated gene in ccRCC patients is Polybromo-1 (PBRM1), a subunit of the SWI/SNF (or BAF for BRG1/BRM associated factors) chromatin remodeling complex, subunits of which are mutated in 20% of human cancers. PBRM1 is characterized by six sequential bromodomains proposed to bind acetylated lysines and is a subunit in a minor BAF subcomplex called PBAF (for Polybromo-1 BAF). The overall goal of this proposal is to determine the mechanism of PBRM1-mediated chromatin targeting of the PBAF complex and how that relates to downstream transcriptional regulation of genes important for tumor suppression in ccRCC. Based on our preliminary data, we hypothesize that several of the six bromodomains of PBRM1 are required for multivalent targeting of the PBAF complex to multiple histone acetylation sites located at genomic regions important for the regulation of genes involved in cell adhesion and epithelial maintenance. In the proposed study we plan to 1) Use cellular assays and animal models to confirm and characterize PBRM1 as a tumor suppressor involved in the regulation of cell adhesion, 2) Define how PBRM1 status predicts therapeutic efficacy of established and proposed ccRCC drugs, 3) Identify genomic binding sites for PBRM1 in ccRCC and the transcriptional regulation by PBAF-mediated chromatin remodeling, and 4) Define the histone acetylation marks responsible for specific recruitment of PBRM1 and PBAF. The proposed study will greatly increase our understanding of the mechanisms involved in renal tumorigenesis and expand our understanding of the tumor suppressive mechanisms of BAF-mediated chromatin remodeling. It is our belief that this study will provide direct evidence of novel therapeutic targets for treating renal cancer.
The proposed research is relevant to public health because discovery of epigenetic mechanisms that drive renal clear cell carcinoma will establish new avenues of investigation to treat patients with metastatic disease. Thus, the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer disease.