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

Authors
 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 
Citation
 NATURE CELL BIOLOGY, Vol.25(5) : 765-777, 2023-05 
Journal Title
NATURE CELL BIOLOGY
ISSN
 1465-7392 
Issue Date
2023-05
MeSH
Carcinoma, Renal Cell* / genetics ; Carcinoma, Renal Cell* / metabolism ; Chromatin / genetics ; Chromosomal Proteins, Non-Histone / genetics ; DNA Helicases / genetics ; DNA-Binding Proteins / genetics ; Genomics ; Humans ; Kidney Neoplasms* / metabolism ; NF-kappa B / genetics ; Nuclear Proteins / genetics ; Transcription Factors / genetics
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. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Full Text
https://www.nature.com/articles/s41556-023-01122-y
DOI
10.1038/s41556-023-01122-y
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/198093
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