BRD4 regulates metastatic potential of castration-resistant prostate cancer through AHNAK

Jordan S. Shafran, Guillaume P. Andrieu, Balázs Györffy, Gerald V. Denis

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen deprivation therapy (ADT) and accumulated resistance strategies to evade androgen receptor (AR) suppression. In prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation, and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogeneous, ADT-resistant tumor. Here, we examined prostate cancer cell lines that model common castration-resistant prostate cancer (CRPC) subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and Extraterminal (BET) family of proteins. We found that BRD4 regulates cell migration across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate migration and invasion in less aggressive models that retain AR expression or signaling. BRD4, a coregulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits metastatic potential. Overall, these results reveal a novel BRD4–AHNAK pathway that may be targetable to treat metastatic CRPC (mCRPC).

Original languageEnglish
Pages (from-to)1627-1638
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Aug 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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