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

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dc.contributor.author라선영-
dc.contributor.authorAndrew Futreal-
dc.date.accessioned2024-02-15T06:58:14Z-
dc.date.available2024-02-15T06:58:14Z-
dc.date.issued2023-05-
dc.identifier.issn1465-7392-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/198093-
dc.description.abstractPBRM1 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherMacmillan Magazines Ltd.-
dc.relation.isPartOfNATURE CELL BIOLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHCarcinoma, Renal Cell* / genetics-
dc.subject.MESHCarcinoma, Renal Cell* / metabolism-
dc.subject.MESHChromatin / genetics-
dc.subject.MESHChromosomal Proteins, Non-Histone / genetics-
dc.subject.MESHDNA Helicases / genetics-
dc.subject.MESHDNA-Binding Proteins / genetics-
dc.subject.MESHGenomics-
dc.subject.MESHHumans-
dc.subject.MESHKidney Neoplasms* / metabolism-
dc.subject.MESHNF-kappa B / genetics-
dc.subject.MESHNuclear Proteins / genetics-
dc.subject.MESHTranscription Factors / genetics-
dc.titlePBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorXiaosai Yao-
dc.contributor.googleauthorJing Han Hong-
dc.contributor.googleauthorAmrita M Nargund-
dc.contributor.googleauthorMichelle Shu Wen Ng-
dc.contributor.googleauthorHong Lee Heng-
dc.contributor.googleauthorZhimei Li-
dc.contributor.googleauthorPeiyong Guan-
dc.contributor.googleauthorMasahiro Sugiura-
dc.contributor.googleauthorPek Lim Chu-
dc.contributor.googleauthorLoo Chien Wang-
dc.contributor.googleauthorXiaofen Ye-
dc.contributor.googleauthorJames Qu-
dc.contributor.googleauthorXiu Yi Kwek-
dc.contributor.googleauthorJeffrey Chun Tatt Lim-
dc.contributor.googleauthorWen Fong Ooi-
dc.contributor.googleauthorJoanna Koh-
dc.contributor.googleauthorZhenxun Wang-
dc.contributor.googleauthorYou-Fu Pan-
dc.contributor.googleauthorYan Shan Ong-
dc.contributor.googleauthorKiat-Yi Tan-
dc.contributor.googleauthorJian Yuan Goh-
dc.contributor.googleauthorSheng Rong Ng-
dc.contributor.googleauthorLuca Pignata-
dc.contributor.googleauthorDachuan Huang-
dc.contributor.googleauthorAlexander Lezhava-
dc.contributor.googleauthorSu Ting Tay-
dc.contributor.googleauthorMinghui Lee-
dc.contributor.googleauthorXun Hui Yeo-
dc.contributor.googleauthorWai Leong Tam-
dc.contributor.googleauthorSun Young Rha-
dc.contributor.googleauthorShang Li-
dc.contributor.googleauthorErnesto Guccione-
dc.contributor.googleauthorAndrew Futreal-
dc.contributor.googleauthorJing Tan-
dc.contributor.googleauthorJoe Poh Sheng Yeong-
dc.contributor.googleauthorWanjin Hong-
dc.contributor.googleauthorRobert Yauch-
dc.contributor.googleauthorKenneth Tou-En Chang-
dc.contributor.googleauthorRadoslaw M Sobota-
dc.contributor.googleauthorPatrick Tan-
dc.identifier.doi10.1038/s41556-023-01122-y-
dc.contributor.localIdA01316-
dc.relation.journalcodeJ02291-
dc.identifier.eissn1476-4679-
dc.identifier.pmid37095322-
dc.identifier.urlhttps://www.nature.com/articles/s41556-023-01122-y-
dc.contributor.alternativeNameRha, Sun Young-
dc.contributor.affiliatedAuthor라선영-
dc.citation.volume25-
dc.citation.number5-
dc.citation.startPage765-
dc.citation.endPage777-
dc.identifier.bibliographicCitationNATURE CELL BIOLOGY, Vol.25(5) : 765-777, 2023-05-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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