BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer.
Animals
Azepines
/ pharmacology
Benzamides
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Chromosomal Proteins, Non-Histone
/ physiology
Gene Expression Regulation, Neoplastic
/ physiology
Humans
Male
Mice
Mice, SCID
Nitriles
Phenylthiohydantoin
/ analogs & derivatives
Prostatic Neoplasms, Castration-Resistant
/ genetics
Protein Biosynthesis
Receptors, Androgen
/ metabolism
Transcription Factors
/ antagonists & inhibitors
Transcription, Genetic
Triazoles
/ pharmacology
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
09
11
2018
accepted:
19
03
2019
revised:
15
03
2019
pubmed:
19
4
2019
medline:
15
2
2020
entrez:
19
4
2019
Statut:
ppublish
Résumé
BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.
Identifiants
pubmed: 30996246
doi: 10.1038/s41388-019-0815-5
pii: 10.1038/s41388-019-0815-5
pmc: PMC6677126
mid: NIHMS1041761
doi:
Substances chimiques
(+)-JQ1 compound
0
AR protein, human
0
Azepines
0
BRD4 protein, human
0
Benzamides
0
CBX3 protein, human
0
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
Nitriles
0
Receptors, Androgen
0
Transcription Factors
0
Triazoles
0
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5658-5669Subventions
Organisme : NLM NIH HHS
ID : K01 LM012877
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178610
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA069533
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000128
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
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