PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs, heightening NF-κB activity in PBRM1-deficient models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of pre-existing and newly acquired RELA specific to PBRM1 loss, activating downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumours. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumourigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.

PBRM1编码 PBAF SWI/SNF 染色质重塑子的辅助亚基，PBRM1 失活是肾癌中的常见事件。然而，PBRM1 丢失对染色质重塑的影响尚未得到充分研究。在这里，我们发现，在 VHL 缺陷的肾肿瘤中，PBRM1 缺陷导致异位 PBAF 复合物定位于从头基因组位点，激活促肿瘤 NF-κB 通路。PBRM1 缺陷的 PBAF 复合物保留了 SMARCA4 和 ARID2 之间的关联，但与 BRD7 的连接松散。PBAF 复合物从启动子近端区域重新分布到含有 NF-κB 基序的远端增强子，从而增强 PBRM1 缺陷模型和临床样本中的 NF-κB 活性。SMARCA4 的 ATP 酶功能维持染色质占据预先存在的和新获得的针对 PBRM1 丢失的 RELA，激活下游靶基因表达。蛋白酶体抑制剂硼替佐米消除 RELA 占据，抑制 NF-κB 激活并延迟 PBRM1 缺陷肿瘤的生长。总之，PBRM1 通过残留的 PBRM1 缺陷型 PBAF 复合物抑制促肿瘤 NF-κB 靶基因的异常释放来保护染色质。