Genome-wide chromatin profiles of PBRM1 [RNA-Seq]
PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler. The inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. Here we show that in VHL-deficient ccRCC tumors, PBRM1 loss results in an altered PBAF complex that retains the association between SMARCA4 and ARID2 but disengages BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proxy regions to distal enhancer regions. The ATPase function of SMARCA4 enhances the recruitment of nuclear factor RELA to aberrant sites and promotes NF-?B activity. Proteasome inhibitor bortezomib reverses NF-?B activation by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-?B target genes by residual PBRM1-deficient PBAF complexes. Overall design: Comparison of transcriptomic changes with and without PBRM1