25855

BRMS1

-;breast cancer metastasis suppressor 1;BRMS1;breast cancer metastasis suppressor 1

breast cancer metastasis-suppressor 1

11q13.2

protein-coding

The majority of patients with lung cancer present with metastatic disease. Chronic inflammation and subsequent activation of nuclear factor-kappaB (NF-kappaB) have been associated with the development of cancers. The RelA/p65 subunit of NF-kappaB 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-kappaB-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-kappaB can regulate metastatic disease, and offers a potential target for newer-generation epigenetic oncopharmaceuticals.