Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer
| Autor: | Ying Li, Viacheslav M. Morozov, Matthew M Clowers, Alexander M. Ishov |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty castration resistant prostate cancer medicine.drug_class JMJD3/UTX urologic and male genital diseases 03 medical and health sciences Prostate cancer GSK-J4 0302 clinical medicine Transcription (biology) Internal medicine medicine Epigenetics Demethylation Cabazitaxel biology business.industry medicine.disease Androgen 3. Good health Androgen receptor 030104 developmental biology Endocrinology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Demethylase H3K27Me2/3 business Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.19100 |
| Popis: | // Viacheslav M. Morozov 1 , Ying Li 1, 3 , Matthew M. Clowers 2 and Alexander M. Ishov 1 1 Department of Anatomy and Cell Biology and Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA 2 Department of Cellular and Molecular Biology, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA 3 IDP 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. |
| Databáze: | OpenAIRE |
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