title: Selective inhibition of tumor oncogenes by disruption of super-enhancers.
abstract: Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Lovén
authors.forename: Heather A
authors.initials: HA
authors.lastname: Hoke
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.forename: Ashley
authors.initials: A
authors.lastname: Lau
authors.forename: David A
authors.initials: DA
authors.lastname: Orlando
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Tong Ihn
authors.initials: TI
authors.lastname: Lee
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D006801:Humans; D056892:Mediator Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D056892:Mediator Complex; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins