查看文章

PBRM1 is the 2 nd-most frequently deleted and mutated gene in clear cell renal cell cancers (RCC). How this loss promotes malignancy is poorly understood. PBRM1 is a subunit of the PBAF coactivator complex that transcription factors recruit to reposition nucleosomes for gene activation. Identifying transcription factors using PBRM1/PBAF might therefore indicate gene expression programs repressed by PBRM1 loss. We therefore used affinity-purification mass spectrometry to identify, in unbiased fashion, transcription factors recruiting PBRM1 in kidney lineage cells. These unbiased proteomic analyses identified PAX8, a master transcription factor essential for kidney epithelial fates, as the most prominent PBRM1 interaction partner. Reverse proteomic analyses of the PAX8 protein hub confirmed recruitment specifically of PBRM1/PBAF, and not the BAF coactivator complex. More conspicuous in the PAX8 hub in RCC cells, however, were several corepressors, eg DNMT1, which oppose coactivators to repress instead of activate genes. Accordingly, key PAX8 target genes, eg, GATA3, LHX1, WT1, and> 500 other kidney epithelial genes, were repressed and hyper-methylated in RCC versus normal kidney, with the greatest repression in cases with bi-allelic PBRM1 inactivation. PBRM1 re-introduction into RCC cells, or depletion of the corepressor DNMT1 using a clinical drug decitabine, rebalanced both composition and function of the PAX8 transcription factor hub toward coactivators, activating terminal epithelial fates in vitro and in vivo. Thus, PBRM1 coactivator loss skews composition of the PAX8 kidney lineage master transcription factor hub …