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

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. C4-2B cells were treated with vehicle or the small molecule IliA (5 μM) and IliA (10 μM), for 48 h before RNA extraction. RNA-seq libraries were from 1 μg total RNA which was extracted using the total RNA isolation kit (Tiangen, BJ, China) and reverse transcribed with reverse transcriptase M-MLV (Takara, DL, China), according to the manufacturer's instructions. Libraries were validated with an Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA).