학술논문
PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma
Document Type
Article
Author
Yao, Xiaosai; Hong, Jing Han; Nargund, Amrita M.; Ng, Michelle Shu Wen; Heng, Hong Lee; Li, Zhimei; Guan, Peiyong; Sugiura, Masahiro; Chu, Pek Lim; Wang, Loo Chien; Ye, Xiaofen; Qu, James; Kwek, Xiu Yi; Lim, Jeffrey Chun Tatt; Ooi, Wen Fong; Koh, Joanna; Wang, Zhenxun; Pan, You-Fu; Ong, Yan Shan; Tan, Kiat-Yi; Goh, Jian Yuan; Ng, Sheng Rong; Pignata, Luca; Huang, Dachuan; Lezhava, Alexander; Tay, Su Ting; Lee, Minghui; Yeo, Xun Hui; Tam, Wai Leong; Rha, Sun Young; Li, Shang; Guccione, Ernesto; Futreal, Andrew; Tan, Jing; Yeong, Joe Poh Sheng; Hong, Wanjin; Yauch, Robert; Chang, Kenneth Tou-En; Sobota, Radoslaw M.; Tan, Patrick; Teh, Bin Tean
Source
Nature Cell Biology; 20230101, Issue: Preprints p1-13, 13p
Subject
Language
ISSN
14657392; 14764679
Abstract
PBRM1encodes 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.