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

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 p...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Signal Transduction Source Type: research