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BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy.

Authors: Segura, MF  Fontanals-Cirera, B  Gaziel-Sovran, A  Guijarro, MV  Hanniford, D  Zhang, G  Gonzalez-Gomez, P  Morante, M  Jubierre, L  Zhang, W  Darvishian, F  Ohlmeyer, M  Osman, I  Zhou, MM  Hernando, E 
Citation: Segura MF, etal., Cancer Res. 2013 Oct 15;73(20):6264-76. doi: 10.1158/0008-5472.CAN-13-0122-T. Epub 2013 Aug 15.
Pubmed: (View Article at PubMed) PMID:23950209
DOI: Full-text: DOI:10.1158/0008-5472.CAN-13-0122-T

Metastatic melanoma remains a mostly incurable disease. Although newly approved targeted therapies are efficacious in a subset of patients, resistance and relapse rapidly ensue. Alternative therapeutic strategies to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell identity are emerging. Bromodomain and extraterminal domain (BET) proteins are epigenome readers known to exert key roles at the interface between chromatin remodeling and transcriptional regulation. Here, we report that BRD4, a BET family member, is significantly upregulated in primary and metastatic melanoma tissues compared with melanocytes and nevi. Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor-treated cells followed by Gene Ontology analysis showed a striking impact on transcriptional programs controlling cell growth, proliferation, cell-cycle regulation, and differentiation. In particular, we found that, rapidly after BET displacement, key cell-cycle genes (SKP2, ERK1, and c-MYC) were downregulated concomitantly with the accumulation of cyclin-dependent kinase (CDK) inhibitors (p21 and p27), followed by cell-cycle arrest. Importantly, BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status, opening the possibility of using these small-molecule compounds to treat patients for whom no effective targeted therapy exists. Collectively, our study reveals a critical role for BRD4 in melanoma tumor maintenance and renders it a legitimate and novel target for epigenetic therapy directed against the core transcriptional program of melanoma.

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CRRD Object Information
CRRD ID: 9586346
Created: 2014-09-29
Species: All species
Last Modified: 2014-09-29
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.