Role of GATA2 in the AR Transcriptional Program in Prostate Cancer

Our lab has been studying the role of the transcription factor GATA2 as a regulator of androgen receptor (AR) signaling and a novel therapeutic target in prostate cancer (PrCa). GATA2 is considered a pioneer factor for the AR: GATA2 co-localizes with the AR on chromatin and is critical for priming the chromatin to allow AR to bind and become transcriptionally active (Fig. 1). Increased GATA2 expression has been correlated with poor prognosis and more aggressive cancers, and has been implicated as a potential driving gene in metastatic PrCa, as evidenced in patient expression data as well as cell phenotypic assessments, which demonstrated that silencing GATA2 decreases cell migration, tissue invasion and focal adhesion. Interestingly, in studies looking at ETS factor reprogramming of the AR after deletion of PTEN (which is common in PrCa), there is an even greater number of new AR binding sites on chromatin that contain the GATA2 DNA binding motif. 

We have discovered that GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin (Fig. 2-3) to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex (He at al. PNAS 2014).

Role of GATA2 in the Expression of AR in PrCa

Our lab recently demonstrated that GATA2 directly promotes AR expression (both full-length and its splice variant). This was confirmed by a strong positive correlation between GATA2 and AR expression in prostate cancer (cell lines and patient specimens). We found high GATA2 expression and transcriptional activity to be predictive of worse clinical outcome in PrCa patients. We also found that GATA2 silencing results in decrease in both AR mRNA and protein levels in androgen-free and androgen-treated cells, diminishing the expression of not only full length AR, but also its splice variant ARv7 (He et al. PNAS 2014). 

The direct regulation of AR gene expression by GATA2 is attributable to recruitment of GATA2 to the extended promoter region of the AR gene (~5.5 kb upstream of the TSS), which also serves as the basis for a negative autoregulatory feedback loop of AR expression. We observed that androgen suppresses GATA2 mRNA and protein levels, which decreases GATA2 recruitment to the AR gene promoter. Androgen deprivation induces GATA2 expression, which, in turn, can upregulate AR mRNA. This negative feedback loop between GATA2 and AR can contribute to the increased AR expression seen in many CRPCs (Fig. 4).

Therapeutic Directions

In addition to the above critical role of GATA2 in AR signaling, GATA2 has also been reported to regulate IGF-2 expression in PrCa cells, resulting in the downstream activation of AR-independent genes vital for chemoresistance. Taken together, these findings suggest a potential critical role for GATA2 in both AR-dependent and AR-independent signaling and thus making it an attractive and promising candidate for PrCa therapeutics. 

We found that the GATA2 small molecule inhibitor K-7174 suppresses the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PrCa cell lines (He et al. 2014). Currently, we are pursuing this pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in castration resistance prostate cancer patients (Foley et al. Horm Cancer. 2016).

References

1: He B, Lanz RB, Fiskus W, Geng C, Yi P, Hartig SM, Rajapakshe K, Shou J, Wei L, Shah SS, Foley C, Chew SA, Eedunuri VK, Bedoya DJ, Feng Q, Minami T, Mitsiades CS, Frolov A, Weigel NL, Hilsenbeck SG, Rosen DG, Palzkill T, Ittmann MM, Song Y, Coarfa C, O'Malley BW, Mitsiades N. GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex. Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18261-6. doi: 10.1073/pnas.1421415111. Epub 2014 Dec 8. PubMed PMID: 25489091; PubMed Central PMCID: PMC4280633. 

2: Foley C, Mitsiades N. Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer. Horm Cancer. 2016 Jan 4. [Epub ahead of print] PubMed PMID: 26728473.