The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer.
Androgen Antagonists
/ pharmacology
Cell Line, Tumor
Chromatin
/ drug effects
GATA2 Transcription Factor
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Genetic Variation
/ drug effects
HEK293 Cells
Humans
Male
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Protein Domains
/ genetics
Receptors, Androgen
/ genetics
Transcriptional Activation
/ drug effects
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
16
11
2018
revised:
25
01
2019
accepted:
28
02
2019
pubmed:
6
3
2019
medline:
2
5
2020
entrez:
6
3
2019
Statut:
ppublish
Résumé
The androgen receptor (AR) is a key driver of prostate cancer development. Antiandrogens effectively inactivate the AR, but subsequent AR reactivation progresses the disease to castrate-resistant prostate cancer (CRPC). Constitutively active AR splice variants (AR-V) that function unchallenged by current AR-targeted therapies are key drivers of CRPC. Currently, very little is known about the regulation of AR-Vs at the chromatin level. Here, we show that the pioneer factor GATA2 is a critical regulator of AR-Vs. Furthermore, we demonstrate that the GATA2 cistrome in CRPC shares considerable overlap with bromodomain and extraterminal (BET) proteins and is codependent for DNA binding. GATA2 activity is compromised by BET inhibitors, which attenuates the pioneering role of GATA2 in CRPC. In all, this study indicates that GATA2 is a critical regulator of AR-V-mediated transactivation and is sensitive to BET inhibitors, signifying these agents may be efficacious in patients with CRPC which overexpress GATA2. IMPLICATIONS: We have defined novel mechanisms of AR-V and GATA2 regulation in advanced prostate cancer that could be therapeutically exploited.
Identifiants
pubmed: 30833300
pii: 1541-7786.MCR-18-1231
doi: 10.1158/1541-7786.MCR-18-1231
doi:
Substances chimiques
AR protein, human
0
Androgen Antagonists
0
Chromatin
0
GATA2 Transcription Factor
0
GATA2 protein, human
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1264-1278Subventions
Organisme : Medical Research Council
ID : MR/P009972/1
Pays : United Kingdom
Informations de copyright
©2019 American Association for Cancer Research.