title: BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion.
abstract: Prostate cancer (PCa) that becomes resistant to hormone castration and next-generation androgen receptor (AR)-targeted therapies, called castration-resistant prostate cancer (CRPC), poses a significant clinical challenge. A better understanding of PCa progression and key molecular mechanisms could bring novel therapies to light. One potential therapeutic target is ERG, a transcription factor aberrantly up-regulated in PCa due to chromosomal rearrangements between androgen-regulated gene TMPRSS2 and ERG. Here we show that the most common PCa-associated truncated ERG T1-E4 (ERGΔ39), encoded by fusion between TMPRSS2 exon 1 and ERG exon 4, binds to bromodomain-1 (BD1) of bromodomain containing protein 4 (BRD4), a member of the bromodomain and extraterminal domain (BET) family. This interaction is partially abrogated by BET inhibitors JQ1 and iBET762. Meta-analysis of published ERG (T1-E4) and BRD4 chromatin immunoprecipitation-sequencing (ChIP-seq) data demonstrates overlap in a substantial portion of their binding sites. Gene expression profile analysis shows some ERG-BRD4 co-target genes are upregulated in CRPC compared to hormone-naïve counterparts. We provide further evidence that ERG-mediated invasion of PCa cells was significantly enhanced by an acetylation-mimicking mutation in ERG that augments the ERG-BRD4 interaction. Our findings reveal that PCa-associated ERG can interact and co-occupy with BRD4 in the genome, and suggest this druggable interaction is critical for ERG-mediated cell invasion and PCa progression.
authors.affiliation: Mayo Graduate School, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Blee
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
mesh_terms: D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C072312:ERG protein, human; C000624329:bromodomain and extra-terminal domain protein, human; C554645:molibresib
keywords: BRD4; ERG; acetylation; bromodomain; cell invasion