title: BET bromodomain inhibitors--a novel epigenetic approach in castration-resistant prostate cancer.
abstract: The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). However, durable responses to these therapies have been limited and there is a need to identify additional therapeutic targets within the AR-signaling network. Recently a group at University of Michigan Medical School outlined the potential for BET bromodomain protein inhibitors as a novel epigenetic approach to treatment of CRPC. In prostate cancer cell lines, BET bromodomain inhibitor, JQ1, was shown to induce apoptosis and down-regulate AR-regulated gene transcription. Bromodomain and the extra-terminal (BET) subfamily of human bromodomain proteins, with a focus on BRD4, were shown to play a major role in AR signaling and interact with AR via bromodomain (BD) 1/2. JQ1 inhibits this BRD4-AR bond, resulting in removal of RNA polymerase II from AR target genes, causing reduced AR gene transcription and subsequent diminished AR signaling. JQ1 lead to a significant reduction in tumor volume and weight in VCaP xenograft mice.
authors.affiliation: a Genitourinary Malignancies Branch; Center for Cancer Research; National Cancer Institute ; Bethesda , MD USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lochrin
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C554645:molibresib
keywords: BET bromodomain inhibitor; androgen receptor; castration-resistant prostate cancer; gene transcription