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

  • Front Pharmacol. 2021 Oct 27:12:723729. doi: 10.3389/fphar.2021.723729.
Lang Guo  1 ,  Xiaowei Luo  2 ,  Ping Yang  3 ,  Yanting Zhang  2 ,  Jialuo Huang  4 ,  Hong Wang  4 ,  Yinfeng Guo  4 ,  Weifeng Huang  4 ,  Zhiqiang Chen  1 ,  Shusheng Wang  1 ,  Junjian Wang  5 ,  Jinping Lei  4 ,  Songtao Xiang  1 ,  Yonghong Liu  2  6
Affiliations
  • 1. Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2. Institute of Marine Drugs/Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning, China.
  • 3. Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 4. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
  • 5. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
  • 6. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
PMID: 34776951 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.

Keywords
androgen receptor; ascochlorin derivatives; castration-resistant prostate cancer (CRPC); enhancer of zeste homolog 2; enzalutamide.
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