Genome-wide chromatin profiles of PBRM1 [ChIP-Seq]
PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in aberrant PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-?B pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7 and redistribute from promoter proximal regions to distal enhancers containing NF-?B motifs. Subsequently, PBRM1-deficient cells display heightened NF-?B activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-?B activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. 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 chromatin changes with and without PBRM1