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The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolin A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows antiproliferative activity in human PCa cells, but its mechanism of action against Castration-resistant prostate cancer is not known. Herein, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses reduced the protein level of EZH2, leading to transcriptional change. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, Ili-A could enhance the anticancer activity of enzalutamide in CRPC cancer models. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPC.