Dual targeting of bromodomain and extra-terminal domain proteins, and WNT or MAPK signaling, inhibits c-MYC expression and proliferation of colorectal cancer cells
- Author(s)
- Togel, L; Nightingale, R; Chueh, AC; Jayachandran, A; Tran, H; Phesse, T; Wu, R; Sieber, OM; Arango, D; Dhillon, AS; Dawson, MA; Diez-Dacal, B; Gahman, TC; Filippakopoulos, P; Shiau, AK; Mariadason, JM;
- 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
- Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- 26983878
- Publisher's Version
- https://doi.org/10.1158/1535-7163.MCT-15-0724
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-04-05 01:44:00
Last Modified: 2017-07-06 11:49:53