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
  • 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. [email protected].
PMID: 26983878 DOI: 10.1158/1535-7163.MCT-15-0724
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.

Products