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Oncogene. 2012 Mar 1;31(9):1143-54. doi: 10.1038/onc.2011.308. Epub 2011 Jul 18.

Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1.

Author information

1
Department of Surgery, University of Virginia, Charlottesville, VA 22908-0679, USA.

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.

PMID:
21765477
PMCID:
PMC3219802
DOI:
10.1038/onc.2011.308
[Indexed for MEDLINE]
Free PMC Article

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