Dual targeting of bromodomain and extra-terminal domain proteins, and WNT or MAPK signaling, inhibits c-MYC expression and proliferation of colorectal cancer cells
Journal Title
Mol Cancer Ther
Publication Type
Journal Article in press
Abstract
Inhibitors of the bromo and extra-terminal domain (BET) protein family attenuate the proliferation of several tumor cell lines. These effects are mediated at least in part through repression of c-MYC. In colorectal cancer (CRC), overexpression of c-MYC due to hyperactive WNT/beta-catenin/TCF signaling is a key driver of tumor progression however effective strategies to target this oncogene remain elusive. Here, we investigated the effect of BET inhibitors (BETi) on CRC cell proliferation and c-MYC expression. Treatment of 20 CRC cell lines with the BETi JQ1 identified a subset of highly sensitive lines. JQ1 sensitivity was higher in cell lines with microsatellite instability, but was not associated with the CpG island methylator phenotype, c-MYC expression or amplification status, BET protein expression, or mutation status of TP53, KRAS/BRAF or PIK3CA/PTEN. Conversely, JQ1 sensitivity correlated significantly with the magnitude of c-MYC mRNA and protein repression. JQ1-mediated c-MYC repression was not due to generalized attenuation of beta-catenin/TCF transcription, as JQ1 had minimal effects on other beta-catenin/TCF target genes or beta-catenin/TCF reporter activity. BETi preferentially target super-enhancer-regulated genes and a super-enhancer in c-MYC was recently identified in HCT116 cells to which BRD4 and effector transcription factors of the WNT/beta-catenin/TCF and MEK/ERK pathways are recruited. Combined targeting of c-MYC with JQ1 and inhibitors of these pathways additively repressed c-MYC and proliferation of HCT116 cells. These findings demonstrate that BETi downregulate c-MYC expression and inhibit CRC cell proliferation, and identify strategies for enhancing the effects of BETi on c-MYC repression by combinatorial targeting the c-MYC super-enhancer.
Publisher
AACR
WEHI Research Division(s)
Systems Biology And Personalised Medicine
PubMed ID
26983878
Rights Notice
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Creation Date: 2016-04-05 01:44:00
Last Modified: 2017-07-06 11:49:53
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