title: Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells.
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.
authors.affiliation: 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.
authors.forename: Lars
authors.initials: L
authors.lastname: Tögel
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nightingale
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Anderly C
authors.initials: AC
authors.lastname: Chueh
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Aparna
authors.initials: A
authors.lastname: Jayachandran
authors.affiliation: 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.
authors.forename: Hoanh
authors.initials: H
authors.lastname: Tran
authors.affiliation: Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: Phesse
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.affiliation: CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.affiliation: Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
authors.forename: Amardeep S
authors.initials: AS
authors.lastname: Dhillon
authors.affiliation: Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.affiliation: Ludwig Institute for Cancer Research and UK and Structural Genomics Consortium, Oxford, United Kingdom.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Diez-Dacal
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Gahman
authors.affiliation: Ludwig Institute for Cancer Research and UK and Structural Genomics Consortium, Oxford, United Kingdom.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, California.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.affiliation: 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.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage* / Q000494:pharmacology; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011728:Pyridones; D011744:Pyrimidinones; D014230:Triazoles; C560077:trametinib