Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer.

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 HOTBIN10 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.

• Authors: 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 Rix, Youngchul Kim, Ranjan Perera, Nicholas J Lawrence, Ernst Schonbrunn, Kiran Mahajan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 12 Pg. 2796-2810 (12 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30242092 (Publication Type: 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.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Androgen Receptor Antagonists
• Androgens
• BRD4 protein, human
• Cell Cycle Proteins
• HOXB13 protein, human
• Homeodomain Proteins
• Nuclear Proteins
• Protein Kinase Inhibitors
• Transcription Factors

Topics

• Androgen Receptor Antagonists (pharmacology)
• Androgens (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Epigenesis, Genetic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Regulatory Networks (drug effects)
• Genetic Loci
• Homeodomain Proteins (metabolism)
• Humans
• Male
• Mice, SCID
• Neoplasm Metastasis
• Nuclear Proteins (metabolism)
• Prostatic Neoplasms, Castration-Resistant (genetics, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Transcription Factors (metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays