Inhibition of enhancer of zeste homolog 2 (EZH2) overcomes enzalutamide resistance in castration-resistant prostate cancer

• Published in: The Journal of biological chemistry 2019-06, Vol.294 (25), p.9911-9923
• Main Authors: Bai, Yunfeng, Zhang, Zhuangzhuang, Cheng, Lijun, Wang, Ruixin, Chen, Xiaoliang, Kong, Yifan, Feng, Feng, Ahmad, Nihal, Li, Lang, Liu, Xiaoqi
• Format: Article
• Language: English
• Subjects: androgen receptor; Animals; Apoptosis; castration-resistant prostate cancer; Cell Proliferation; chemoresistance; drug resistance; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; enzalutamide; EZH2; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mice; Mice, Nude; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - chemistry; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction; Tumor Cells, Cultured; tumor metastasis; Xenograft Model Antitumor Assays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.008152

Enzalutamide, approved by the United States Food and Drug Administration in 2018 for the management of metastatic castration-resistant prostate cancer (CRPC), is an androgen receptor (AR) inhibitor. It blocks androgen binding to the AR, AR nuclear translocation, and AR-mediated DNA binding. Unfortunately, a considerable proportion of tumors eventually develop resistance during the treatment. The molecular mechanisms underlying enzalutamide resistance are not completely understood. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressor complex 2, has been proposed as a prognostic marker for prostate cancer (PCa). With the goal to test whether EZH2 also plays a critical role in acquisition of enzalutamide resistance in CRPC, here we examined whether EZH2 inhibition/depletion enhances the efficacy of enzalutamide in enzalutamide-resistant PCa cells. We show that combining the EZH2 inhibitor GSK126 with enzalutamide synergistically inhibits cell proliferation and colony formation and promotes apoptosis in enzalutamide-resistant PCa cells. EZH2 depletion also overcomes enzalutamide resistance in both cultured cells and xenograft tumors. Mechanistically, we found that EZH2 directly binds to the promoter of prostate-specific antigen and inhibits its expression in enzalutamide-resistant PCa cells. In agreement, bioinformatics analysis of clinical RNA sequencing data involving GSEA indicated a strong correlation between AR and EZH2 gene expression during PCa progression. Our study provides critical insights into the mechanisms underlying enzalutamide resistance, which may offer new approaches to enhance the efficacy of enzalutamide in CRPC.