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Nature Cell Biology

Nature Cell Biology

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PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.

Published:24 April 2023 DOI: 10.1038/s41556-023-01122-y PMID: 37095322
Xiaosai Yao, Jing Han Hong, Amrita M. Nargund, Michelle Shu Wen Ng, Hong Lee Heng, Zhimei Li, Peiyong Guan, Masahiro Sugiura, Pek Lim Chu, Loo Chien Wang, Xiaofen Ye, James Qu, Xiu Yi Kwek, Jeffrey Chun Tatt Lim, Wen Fong Ooi, Joanna Koh, Zhenxun Wang, You-Fu Pan, Yan Shan Ong, Kiat-Yi Tan, Jian Yuan Goh, Sheng Rong Ng, Luca Pignata, Dachuan Huang, Alexander Lezhava, Su Ting Tay, Minghui Lee, Xun Hui Yeo, Wai Leong Tam, Sun Young Rha, Shang Li, Ernesto Guccione, Andrew Futreal, Jing Tan, Joe Poh Sheng Yeong, Wanjin Hong, Robert Yauch, Kenneth Tou-En Chang, Radoslaw M. Sobota, Patrick Tan, Bin Tean Teh

Abstract

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. Yao et al. observe and characterize genomic redistribution of the PBAF complexes upon PBRM1 loss, leading to sustained RELA occupancy by SMARCA4, activation of the NF-kB pathway and enhanced kidney tumourigenesis.

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