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 NF-κB have been associated 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 metastasis suppressor gene promoter via direct recruitment of DNMT-1 to chromatin in response to 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/65 to function as an active transcriptional repressor is promoter specific as the NF-κB-regulated gene cIAP2 is transcriptionally activated while 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.