TY - JOUR
T1 - Targeting the BRD4-HOXB13 coregulated transcriptional networks with bromodomain kinase inhibitors to suppress metastatic castration-resistant prostate cancer
AU - Nerlakanti, Niveditha
AU - Yao, Jiqiang
AU - Nguyen, Duy T.
AU - Patel, Ami K.
AU - Eroshkin, Alexey M.
AU - Lawrence, Harshani R.
AU - Ayaz, Muhammad
AU - Kuenzi, Brent M.
AU - Agarwal, Neha
AU - Chen, Yunyun
AU - Gunawan, Steven
AU - Karim, Rezaul M.
AU - Berndt, Norbert
AU - Puskas, John
AU - Magliocco, Anthony M.
AU - Coppola, Domenico
AU - Dhillon, Jasreman
AU - Zhang, Jingsong
AU - Shymalagovindarajan, Subramaniam
AU - Rix, Uwe
AU - Kim, Youngchul
AU - Perera, Ranjan
AU - Lawrence, Nicholas J.
AU - Schonbrunn, Ernst
AU - Mahajan, Kiran
N1 - Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/12
Y1 - 2018/12
N2 - Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOT-BIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
AB - Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOT-BIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85057585289&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-0602
DO - 10.1158/1535-7163.MCT-18-0602
M3 - Article
C2 - 30242092
AN - SCOPUS:85057585289
SN - 1535-7163
VL - 17
SP - 2796
EP - 2810
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -