PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation
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
Affiliations
Xiaorong Gu
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Francis Enane
Indiana Center for Biomedical Innovation, Indiana University School of Medicine, Indianapolis, IN, USA
Rita Tohme
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Caroline Schuerger
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Tomas Radivoyevitch
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
Yvonne Parker
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Eric Zuberi
Department of Biochemistry, Clemson University, Clemson, SC, USA
Bartlomiej Przychodzen
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Babal Kant Jha
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Daniel Lindner
Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Brian Rini
Department of Hematology and Oncology, Vanderbilt University, Nashville, TN, USA
Yogen Saunthararajah
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; Corresponding author
Summary: 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.
