1. Academic Validation
  2. Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

  • Mol Cancer Ther. 2016 Jun;15(6):1217-26. doi: 10.1158/1535-7163.MCT-15-0724.
Lars Tögel 1 Rebecca Nightingale 1 Anderly C Chueh 2 Aparna Jayachandran 2 Hoanh Tran 1 Toby Phesse 3 Rui Wu 2 Oliver M Sieber 4 Diego Arango 5 Amardeep S Dhillon 6 Mark A Dawson 6 Beatriz Diez-Dacal 7 Timothy C Gahman 8 Panagis Filippakopoulos 7 Andrew K Shiau 8 John M Mariadason 9
Affiliations

Affiliations

  • 1 Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
  • 2 Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
  • 3 Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia.
  • 4 Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  • 5 CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 6 Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
  • 7 Ludwig Institute for Cancer Research and UK and Structural Genomics Consortium, Oxford, United Kingdom.
  • 8 Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, California.
  • 9 Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia. john.mariadason@onjcri.org.au.
Abstract

Inhibitors of the bromodomain and extraterminal 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, overexpression of c-Myc due to hyperactive Wnt/β-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 colorectal Cancer cell proliferation and c-Myc expression. Treatment of 20 colorectal Cancer 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 β-catenin/TCF-mediated transcription, as JQ1 had minimal effects on other β-catenin/TCF target genes or β-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/β-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 colorectal Cancer cell proliferation and identify strategies for enhancing the effects of BETi on c-Myc repression by combinatorial targeting the c-Myc super-enhancer. Mol Cancer Ther; 15(6); 1217-26. ©2016 AACR.

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