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

Lang Guo,Yonghong Liu,Shusheng Wang,Jialuo Huang,Ping Yang,Junjian Wang,Yanting Zhang,Xiaowei Luo,Songtao Xiang,Weifeng Huang,Zhiqiang Chen,Yinfeng Guo,Jinping Lei,Hong Wang

doi:10.3389/fphar.2021.723729

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.

Highlights

Cancer of the prostate gland, known commonly as “prostate cancer” (PCa), is the most commonly diagnosed cancer in men living in the United States PCa is responsible for ∼10% of all cancer-related deaths in men (Siegel et al, 2021)
enhancer of zeste homolog 2 (EZH2) has a pivotal role in the development and progression of PCa, so we examined whether Ilicicolin A (Ili-A) could inhibit survival of CRPC cells by blocking EZH2 signaling
We investigated the functional importance of EZH2 expression in the EZH2 signaling pathway by characterizing the inhibition effect of Ili-A on EZH2 activity

Summary

Introduction

Cancer of the prostate gland, known commonly as “prostate cancer” (PCa), is the most commonly diagnosed cancer in men living in the United States PCa is responsible for ∼10% of all cancer-related deaths in men (Siegel et al, 2021). Surgery or androgendeprivation therapy has become the first-line treatment for PCa patients (Litwin and Tan, 2017). Taxane-based chemotherapies, next-generation antiandrogens, and biosynthesis inhibitors, such as enzalutamide ( named MDV3100), abiraterone acetate, and cabazitaxel, have been administered to patients who developed mCRPC (Litwin and Tan, 2017; Oudard et al, 2017; Thakur et al, 2018). Despite the clinical efficacy of these drugs in mCRPC patients, the almost inevitable emergence of drug resistance hampers a definitive cure, possibly due to amplification or gain-of-function somatic mutations of AR, aberrant posttranslational modification of the AR protein, alternative splicing events that result in hyperactive receptors, and cofactor dysregulation and/or intracrine androgen synthesis (Watson et al, 2015). Considerable effort has been made on improving these weaknesses, but an efficient and efficacious method is lacking

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Conclusion