PBRM1编码PBAF SWI/SNF染色质重塑酶的附属副基因，PBRM1失活是肾癌中频繁发生的事件。然而，PBRM1损失对染色质重塑的影响尚未得到充分的研究。在这里，我们表明，在VHL缺陷性肾肿瘤中，PBRM1缺陷导致外显子PBAF复合物出现在新生基因组位点，激活增癌NF-κB通路。PBRM1缺陷PBAF复合物保持SMARCA4和ARID2之间的关联，但BRD7连接松散。PBAF复合物从启动子附近区域重新分布到包含NF-κB基序的远端增强子，提高PBRM1缺陷模型和临床样本中的NF-κB活性。SMARCA4的ATP酶功能维持与PBRM1损失相关的预先存在和新获得的RELA的染色质占用，激活下游靶基因的表达。蛋白酶体抑制剂博来佐米抑制了RELA的占用，抑制了NF-κB的激活，并延缓了PBRM1缺陷肿瘤的生长。最后，PBRM1通过抑制残留的PBRM1缺陷PBAF复合物对促进肿瘤的NF-κB靶基因进行异常解离来保护染色质。©2023年。作者，独家许可Springer Nature Limited使用。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.