Inhibition of EZH2 by chemo- and radiotherapy agents and small molecule inhibitors induces cell death in castration-resistant prostate cancer
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Changping Wu1,*, Xin Jin2,*, Jing Yang1,2, Yinhui Yang2, Yundong He2, Liya Ding2, Yunqian Pan2, Shuai Chen5, Jingting Jiang1, Haojie Huang2,3,4
1Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
2Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
3Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
4Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
5Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China
*These authors have contributed equally to this work
Jingting Jiang, e-mail: firstname.lastname@example.org
Haojie Huang, e-mail: email@example.com
Keywords: EZH2, small molecule inhibitor, radiation therapy, chemotherapy, castration-resistant prostate cancer
Received: November 13, 2015 Accepted: November 16, 2015 Published: December 07, 2015
Androgen deprivation therapy is the mainstay of treatment of advanced prostate cancer (PCa). However, a significant portion of patients experience disease relapse and tumors ultimately evolve into castration resistant prostate cancer (CRPC), for which there is no cure in the clinic. The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in CRPC. It is unclear whether EZH2 can be a therapeutic target in CRPC. Here, we demonstrated that chemo- and radiotherapy agents such as camptothecin (CPT) and γ irradiation decrease EZH2 expression in various PCa cell lines. We provided evidence that functional p53 and RB proteins are required for CPT- and irradiation-induced downregulation of EZH2 in CRPC cells. We demonstrated that EZH2-specific small molecule inhibitors mitigate CRPC cell growth. We further showed that the EZH2 inhibitor GSK126 inhibits both Polycomb-dependent and -independent functions of EZH2 in PCa cells. Importantly, we found that inhibition of EZH2 by genetic and pharmacological means sensitizes CRPC cells to CPT-induced apoptotic death and growth inhibition in culture and in mice. Our data suggest that concomitant administration of small molecule inhibitors of EZH2 may significantly increase the anti-tumor efficacy of conventional chemo- and radiotherapies in CRPC.
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