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Ilicicolin A Exerts Antitumor Effect in Castration-Resistant Prostate Cancer Via Suppressing EZH2 Signaling Pathway

ABSTRACT: 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.

SUBMITTER: Guo L

PROVIDER: S-EPMC8578973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Ilicicolin-A exert antitumor effect in CRPCa via suppressing EZH2 signaling pathway

Project description: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 (AR) antagonist employed for treatment of metastatic castration-resistant prostate cancer (mCRPCa). A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolinal A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows activity in human PCa cells, but its mechanism of action against CRPCa is not known. Here, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses inhibited the transcriptional activity of EZH2 and AR targets by changing their protein expression. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, low-dose Ili-A showed a synergistic effect with enzalutamide to inhibit survival of CRPCa cells in vitro, and enhanced the anti-cancer effect of enzalutamide on CRPCa xenografts with minimal side-effects. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPCa.

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