PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation.

Autor:	Gu X; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Enane F; Indiana Center for Biomedical Innovation, Indiana University School of Medicine, Indianapolis, IN, USA., Tohme R; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Schuerger C; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Radivoyevitch T; Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA., Parker Y; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Zuberi E; Department of Biochemistry, Clemson University, Clemson, SC, USA., Przychodzen B; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Jha BK; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Lindner D; Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Rini B; Department of Hematology and Oncology, Vanderbilt University, Nashville, TN, USA., Saunthararajah Y; 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: saunthy@ccf.org.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Sep 21; Vol. 36 (12), pp. 109747.
DOI:	10.1016/j.celrep.2021.109747
Abstrakt:	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. Competing Interests: Declaration of interests Intellectual property/royalties: Y.S. has issued patents around tetrahydrouridine, decitabine, and 5-azacytidine and is eligible for royalties. Equity: Y.S. has equity interest in EpiDestiny. Income: none. Consultancy: Y.S. is a consultant to EpiDestiny. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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