GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 51; pp. 18261 - 18266
• Main Authors: He, Bin, Lanz, Rainer B., Fiskus, Warren, Geng, Chuandong, Yi, Ping, Hartig, Sean M., Rajapakshe, Kimal, Shou, John, Wei, Liping, Shah, Shrijal S., Foley, Christopher, Chew, Sue Anne, Eedunuri, Vijay K., Bedoya, Diego J., Feng, Qin, Minami, Takashi, Mitsiades, Constantine S., Frolov, Anna, Weigel, Nancy L., Hilsenbeck, Susan G., Rosen, Daniel G., Palzkill, Timothy, Ittmann, Michael M., Song, Yongcheng, Coarfa, Cristian, O'Malley, Bert W., Mitsiades, Nicholas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-12-2014; National Acad Sciences
• Subjects: Androgen receptors; Androgens; Biological Sciences; Cell lines; Cell Proliferation; Chromatin; Chromatin - metabolism; Correlation analysis; Enhancer Elements, Genetic; GATA2 Transcription Factor - physiology; Genes; Hepatocyte Nuclear Factor 3-alpha - metabolism; Histones; Humans; Male; Messenger RNA; Molecules; Nuclear Receptor Coactivators - metabolism; Prognosis; Prostate cancer; Proteins; Receptors, Androgen - metabolism; Receptors, Androgen - physiology; Signal Transduction; Signatures; Steroid receptors; Transcription, Genetic - physiology; Tumors; steroid receptor coactivator; prostate cancer; GATA2; AR signaling; small molecule inhibitor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1421415111

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 Forkhead 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.
Significance Androgen receptor (AR) signaling is a key driver of prostate cancer (PC), even in the context of resistance to current therapies, creating an unmet need for novel approaches to inhibit AR. We demonstrate that the transcription factor GATA-binding protein 2 (GATA2) is critical for both AR expression and optimal transcriptional activity. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. A GATA2 inhibitor suppressed the expression and transcriptional function of AR (including the constitutively active splice variants) and exerted potent anticancer activity against PC cells. We propose GATA2 inhibition as a previously unexplored approach to extinguish both ligand-dependent and ligand-independent AR transcriptional activity and to improve clinical outcomes for PC patients.