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

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

doi:10.18632/oncotarget.19100

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.

Highlights

Prostate cancer (PCa) is the most common noncutaneous neoplasm in the Western male population and is the second leading cause of cancer mortality in American men [1]
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 androgen receptor (AR)-ΔLBD cells (CRPC model) compared with isogenic AR-WT cells

Summary

Introduction

Prostate cancer (PCa) is the most common noncutaneous neoplasm in the Western male population and is the second leading cause of cancer mortality in American men [1]. Pathologic growth of the prostate is controlled mainly by steroid androgens, locally advanced and metastatic diseases are treated with androgen ablation therapy that aims to suppress testosterone production with hormone agonists, or block androgen receptor (AR) activation with anti-androgens that all bind the AR ligand-binding domain (LBD) [2]. Acquired resistance to the second-generation anti-androgen enzalutamide results from a missense (F876L) mutation in the LBD of AR [6] Another mechanism of CRPC insensitivity to antiandrogens is the expression of AR deletion mutants that lack LBD [7] (ARΔLBD). Clinical data and animal models both confirm that expression of ARΔLBD determines resistance to anti-androgens in CRPC [7]

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