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

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

  • Mol Cancer Ther. 2018 Dec;17(12):2796-2810. doi: 10.1158/1535-7163.MCT-18-0602.
Niveditha Nerlakanti # 1 2,  Jiqiang Yao # 3,  Duy T Nguyen # 1 4,  Ami K Patel # 1,  Alexey M Eroshkin 5,  Harshani R Lawrence 6 7,  Muhammad Ayaz 6,  Brent M Kuenzi 2 7,  Neha Agarwal 1,  Yunyun Chen 3,  Steven Gunawan 7,  Rezaul M Karim 7,  Norbert Berndt 7,  John Puskas 8,  Anthony M Magliocco 8,  Domenico Coppola 1 9,  Jasreman Dhillon 9,  Jingsong Zhang 10,  Subramaniam Shymalagovindarajan 11,  Uwe Rix 7 12,  Youngchul Kim 3,  Ranjan Perera 11,  Nicholas J Lawrence 7 12,  Ernst Schonbrunn 7 12,  Kiran Mahajan 13 4 12
Affiliations

Affiliations

  • 1 Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 2 Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida.
  • 3 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 4 Department of Surgery, Washington University in St. Louis, St. Louis, Missouri.
  • 5 Bioinformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  • 6 Chemical Biology Core, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 7 Department of Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 8 Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 9 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 10 Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 11 Analytical Genomics and Bioinformatics, Sanford Burnham Prebys Discovery Institute, Orlando, Florida.
  • 12 Department of Oncological Sciences, University of South Florida, Tampa, Florida.
  • 13 Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. kiranm@wustl.edu.
  • # Contributed equally.
PMID: 30242092 DOI: 10.1158/1535-7163.MCT-18-0602
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.

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