BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
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Delmore-2011-BET Bromodomain Inhi.pdf
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Author(s)
Delmore, Jake E.
Issa, Ghayas C.
Lemieux, Madeleine E.
Rahl, Peter B.
Shi, Junwei
Jacobs, Hannah M.
Kastritis, Efstathios
Gilpatrick, Timothy
Paranal, Ronald M.
Qi, Jun
Date Issued
September 2011
Journal
Cell
Publisher
Elsevier B.V.
Citation
Delmore, Jake E., Ghayas C. Issa, Madeleine E. Lemieux, Peter B. Rahl, Junwei Shi, Hannah M. Jacobs, Efstathios Kastritis, et al. “BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc.” Cell 146, no. 6 (September 2011): 904–917. © 2011 Elsevier Inc.
Version
Final published version
Abstract
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1016/j.cell.2011.08.017
