PBRM1, a subunit of the PBAF coactivator complex that transcription factors use to activate target genes, is genetically inactivated in almost all clear cell renal cell cancers (RCCs). Using unbiased proteomic analyses, we find that PAX8, a master transcription factor driver of proximal tubule epithelial fates, recruits PBRM1/PBAF. Reverse analyses of the PAX8 interactome confirm recruitment specifically of PBRM1/PBAF and not functionally similar BAF. More conspicuous in the PAX8 hub in RCC cells, however, are corepressors, which functionally oppose coactivators. Accordingly, key PAX8 target genes are repressed in RCC versus normal kidneys, with the loss of histone lysine-27 acetylation, but intact lysine-4 trimethylation, activation marks. Re-introduction of PBRM1, or depletion of opposing corepressors using siRNA or drugs, redress coregulator imbalance and release RCC cells to terminal epithelial fates. These mechanisms thus explain RCC resemblance to the proximal tubule lineage but with suppression of the late-epithelial program that normally terminates lineage-precursor proliferation.
Cell reports. 2021 Sep 21 [Epub]
Xiaorong Gu, Francis Enane, Rita Tohme, Caroline Schuerger, Tomas Radivoyevitch, Yvonne Parker, Eric Zuberi, Bartlomiej Przychodzen, Babal Kant Jha, Daniel Lindner, Brian Rini, Yogen Saunthararajah
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Indiana Center for Biomedical Innovation, Indiana University School of Medicine, Indianapolis, IN, USA., Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA., Department of Biochemistry, Clemson University, Clemson, SC, USA., Department of Hematology and Oncology, Vanderbilt University, Nashville, TN, USA., Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: .