Targeting the BRD4-HOXB13 coregulated transcriptional networks with bromodomain kinase inhibitors to suppress metastatic castration-resistant prostate cancer

Niveditha Nerlakanti, Jiqiang Yao, Duy T. Nguyen, Ami K. Patel, Alexey M. Eroshkin, Harshani R. Lawrence, Muhammad Ayaz, Brent M. Kuenzi, Neha Agarwal, Yunyun Chen, Steven Gunawan, Rezaul M. Karim, Norbert Berndt, John Puskas, Anthony M. Magliocco, Domenico Coppola, Jasreman Dhillon, Jingsong Zhang, Subramaniam Shymalagovindarajan, Uwe RixYoungchul Kim, Ranjan Perera, Nicholas J. Lawrence, Ernst Schonbrunn, Kiran Mahajan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2796-2810
Number of pages15
JournalMolecular Cancer Therapeutics
Volume17
Issue number12
DOIs
StatePublished - Dec 2018

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