title: JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms.
abstract: Bromodomain and extra-terminal domain (BET) family proteins are representative epigenetic modulators that read acetylated lysine residues and transfer cellular signals. Recently, the BET protein inhibitor JQ1 was developed and has been extensively studied in many cancer cell types. We demonstrated that JQ1 effectively suppressed the MYC-AP4 axis and induced antitumorigenic effects by targeting a bidirectional positive loop between MYC and AP4 which was first proposed in the present study. MYC and AP4 are the direct targets of BRD4, as demonstrated by chromatin immunoprecipitation (ChIP) assay and BRD4 loss-of-function experiments. Although inhibition of the MYC/MAC dimer suppressed AP4, the efficacy of suppression was not as effective as BRD4 inhibition. Notably, AP4 loss-of-function studies demonstrated that AP4 is a major critical target of JQ1 and that MYC is a novel downstream target of AP4, as demonstrated by AP4 binding to the MYC promoter. Taken together, our results suggest that the epigenetic reader BRD4 is a key mediator of the activated MYC-AP4 axis, which supports the possibility that targeting BET protein is a novel therapeutic strategy for MYC-AP4 axis-activated cancers.
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Sung Kyung
authors.initials: SK
authors.lastname: Choi
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Seong Hwi
authors.initials: SH
authors.lastname: Hong
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Hyuk Soon
authors.initials: HS
authors.lastname: Kim
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Functional RNomics Research Center, College of Medicine, Catholic University, Seoul 137-701, Republic of Korea.
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.affiliation: School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human; C404766:REPIN1 protein, human