title: Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1.
abstract: The majority of patients with lung cancer present with metastatic disease. Chronic inflammation and subsequent activation of nuclear factor-κB (NF-κB) have been associated with the development of cancers. The RelA/p65 subunit of NF-κB is typically associated with transcriptional activation. In this report we show that RelA/p65 can function as an active transcriptional repressor through enhanced methylation of the BRMS1 (breast cancer metastasis suppressor 1) metastasis suppressor gene promoter via direct recruitment of DNMT-1 (DNA (cytosine-5)-methyltransferase 1) to chromatin in response to tumor necrosis factor (TNF). TNF-mediated phosphorylation of S276 on RelA/p65 is required for RelA/p65-DNMT-1 interactions, chromatin loading of DNMT-1 and subsequent BRMS1 promoter methylation and transcriptional repression. The ability of RelA/p65 to function as an active transcriptional repressor is promoter specific, as the NF-κB-regulated gene cIAP2 (cellular inhibitor of apoptosis 2) is transcriptionally activated whereas BRMS1 is repressed under identical conditions. Small-molecule inhibition of either of the minimal interacting domains between RelA/p65-DNMT-1 and RelA/p65-BRMS1 promoter abrogates BRMS1 methylation and its transcriptional repression. The ability of RelA/p65 to directly recruit DNMT-1 to chromatin, resulting in promoter-specific methylation and transcriptional repression of tumor metastasis suppressor gene BRMS1, highlights a new mechanism through which NF-κB can regulate metastatic disease, and offers a potential target for newer-generation epigenetic oncopharmaceuticals.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA 22908-0679, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: M W
authors.initials: MW
authors.lastname: Mayo
authors.forename: A S
authors.initials: AS
authors.lastname: Nagji
authors.forename: P W
authors.initials: PW
authors.lastname: Smith
authors.forename: C S
authors.initials: CS
authors.lastname: Ramsey
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: D R
authors.initials: DR
authors.lastname: Jones
mesh_terms: D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins; D012694:Serine / Q000378:metabolism; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D048069:Tumor Necrosis Factors / Q000494:pharmacology
chemical_list: C410024:BRMS1 protein, human; D002843:Chromatin; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D048069:Tumor Necrosis Factors; D012694:Serine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human