GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

Bin He, Rainer B. Lanz, Warren Fiskus, Chuandong Geng, Ping Yi, Sean M. Hartig, Kimal Rajapakshe, John Shou, Liping Wei, Shrijal S. Shah, Christopher Foley, Sue Anne Chew, Vijay K. Eedunuri, Diego J. Bedoya, Qin Feng, Takashi Minami, Constantine S. Mitsiades, Anna Frolov, Nancy L. Weigel, Susan G. HilsenbeckDaniel G. Rosen, Timothy Palzkill, Michael M. Ittmann, Yongcheng Song, Cristian Coarfa, Bert W. O'Malley, Nicholas Mitsiades

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Fork-head box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.

Original languageEnglish (US)
Pages (from-to)18261-18266
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number51
DOIs
StatePublished - Dec 23 2014

Keywords

  • AR signaling
  • GATA2
  • Prostate cancer
  • Small molecule inhibitor
  • Steroid receptor coactivator

ASJC Scopus subject areas

  • General

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