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GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

2014; National Academy of Sciences; Volume: 111; Issue: 51 Linguagem: Inglês

10.1073/pnas.1421415111

1091-6490

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 Kumar Eedunuri, Diego Bedoya, Qin Feng, Takashi Minami, Constantine S. Mitsiades, Anna Frolov, Nancy L. Weigel, Susan G. Hilsenbeck, Daniel Rosen, Timothy Palzkill, Michael Ittmann, Yongcheng Song, Cristian Coarfa, Bert W. O’Malley, Nicholas Mitsiades,

Estrogen and related hormone effects

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.