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

Oncogene volume 31, pages 1143–1154 (2012)Cite this article

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.

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Acknowledgements

This work was supported by grants R01 CA136705 (to DRJ), R01 CA104397 (to MWM) and R01 CA132580 (to MWM). In addition, this project was supported in part by a gift provided to the University of Virginia by Philip Morris USA. The review and approval process was overseen by an independent National External Advisory Board without any affiliation with the University, Philip Morris USA or any other tobacco company.

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Authors and Affiliations

  1. Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Y Liu, A S Nagji, P W Smith & D R Jones

  2. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA

    M W Mayo, C S Ramsey & D Li

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Correspondence to D R Jones.

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Liu, Y., Mayo, M., Nagji, A. et al. Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1. Oncogene 31, 1143–1154 (2012). https://doi.org/10.1038/onc.2011.308

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