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

• DOI: 10.1016/j.celrep.2021.109747
• Publication Date: 2021-09-21T14:50:12Z
• Authors: Xiaorong Gu; Francis Enane; Rita Tohme; Caroline Schuerger; Tomas Radivoyevitch; Yvonne Parker; Eric Zuberi; Bartlomiej Przych...; Babal Kant Jha; Daniel Lindner; Brian Rini; Yogen Saunthararajah
• Keywords: Male; Transcriptional Activation; 0301 basic medicine; QH301-705.5; Mice, Nude; MYC; renal cell cancer; Master transcription factor; Article; PBRM1; Histones; Kidney Tubules, Proximal; Mice; PAX8 Transcription Factor; 03 medical and health sciences; Epithelial differentiation; Cell Line, Tumor; Animals; Humans; Protein Interaction Maps; Biology (General); RNA, Small Interfering; Carcinoma, Renal Cell; Corepressor; Cell Proliferation; Renal cell cancer; Cell Differentiation; PAX8; epithelial differentiation; coactivator; Kidney Neoplasms; 3. Good health; DNA-Binding Proteins; Mutagenesis; Coactivator; Nephric lineage; RNA Interference; Transcription Factors

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.