Oncotarget

Research Papers:

Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer

Viacheslav M. Morozov, Ying Li, Matthew M. Clowers and Alexander M. Ishov _

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Oncotarget. 2017; 8:62131-62142. https://doi.org/10.18632/oncotarget.19100

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Abstract

Viacheslav M. Morozov1, Ying Li1,3, Matthew M. Clowers2 and Alexander M. Ishov1

1Department of Anatomy and Cell Biology and Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA

2Department of Cellular and Molecular Biology, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA

3IDP Graduate Program, University of Florida College of Medicine, Gainesville, FL 32610, USA

Correspondence to:

Alexander M. Ishov, email: ishov@ufl.edu

Keywords: castration resistant prostate cancer, JMJD3/UTX, H3K27Me2/3, Cabazitaxel, GSK-J4

Received: April 28, 2017    Accepted: May 30, 2017    Published: July 08, 2017

ABSTRACT

Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC.

Reduction of the repressive epigenetic modification H3K27me2/3 correlates with PCa aggressiveness, while corresponding demethylases JMJD3/UTX are overexpressed in PCa. We found that JMJD3/UTX inhibitor GSK-J4 reduced more efficiently proliferation of AR-ΔLBD cells (CRPC model) compared with isogenic AR-WT cells. Inhibition of JMJD3/UTX protects demethylation of H3K27Me2/3, thus reducing levels of H3k27Me1. We observed that the reduction dynamics of H3K27Me1 was faster and achieved at lower inhibitor concentrations in AR-ΔLBD cells, suggesting that inhibition of JMJD3/UTX diminished proliferation of these cells by hindering AR-driven transcription. In addition, we observed synergy between GSK-J4 and Cabazitaxel, a taxane derivative that is approved for CRPC treatment. Collectively, our results point at the H3K27 demethylation pathway as a new potential therapeutic target in CRPC patients.


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