Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Authors: Kaochar, Salma; Rusin, Aleksandra; Foley, Christopher; Rajapakshe, Kimal; Robertson, Matthew; Skapura, Darlene; Mason, Cammy; Berman De Ruiz, Karen; Tyryshkin, Alexey Mikhailovich; Deng, Jenny; Shin, Jin Na; Fiskus, Warren; Dong, Jianrong; Huang, Shixia; Navone, Nora M; Davis, Christel M; Ehli, Erik A; Coarfa, Cristian; Mitsiades, Nicholas

Published In Endocr Relat Cancer, (2021 Nov 24)

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.

PubMed ID: 34636746 Exiting the NIEHS site

MeSH Terms: Cell Line, Tumor; Chromatin; Dilazep/therapeutic use; GATA2 Transcription Factor/genetics; GATA2 Transcription Factor/metabolism; Gene Expression Regulation, Neoplastic; Humans; Male; Oncogenes; Prostatic Neoplasms, Castration-Resistant*/genetics; Receptors, Androgen/metabolism

Back
to Top