Abstract
Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.
Highlights
In 2021, prostate cancer is predicted to cause the death of 34,130 US men, making it the second leading cause of cancer death in American men, after lung cancer (Siegel et al 2021)
The MDVR cells express higher levels of several cancer drivers compared to parental LNCaP cells (Supplementary Fig. 2), including SOX9 (an important transcription factor and Castration-resistant prostate cancer (CRPC) driver (Wang et al 2008, Ma et al 2016)), YAP1 (Kuser-Abali et al 2015), HER3 (Soler et al 2009), phospho-Akt, SRC-3 (an important transcriptional coactivator (Zhou et al 2005, Geng et al 2013, Foley & Mitsiades 2016)), and EZH2 (Varambally et al 2002, Bryant et al 2007, Yu et al 2010, Xu et al 2012)
Novel therapeutic targets are needed in CRPC, in order to improve patient outcomes
Summary
In 2021, prostate cancer is predicted to cause the death of 34,130 US men, making it the second leading cause of cancer death in American men, after lung cancer (Siegel et al 2021) This represents a 30.6% increase in mortality compared to 2016, highlighting the unmet need for effective therapies. The effects of GATA2 can be exerted at several steps of the AR signaling axis, including functioning as a pioneer factor (that facilitates AR to access chromatin and initiate transcription (Wang et al 2007), inducing AR gene expression (He et al 2014, Wu et al 2014) and post-translationally promoting the activity of both full-length and splice-variant AR by enhancing recruitment of steroid receptor coactivators to AR (He et al 2014, Zhao et al 2016). As high GATA2 expression and transcriptional activity are linked to poor prognosis in PC (Chiang et al 2014, He et al 2014), and GATA2 being considered a transcriptional partner and coactivator for AR, GATA2 is poised as a promising therapeutic target for the inhibition of advanced CRPC
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