Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo
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Shou-Hung Tang1, Hsu-Shan Huang2, Hong-Ui Wu3, Yi-Ta Tsai4, Mei-Jen Chuang1, Cheng-Ping Yu5, Shih-Ming Huang6, Guang-Huan Sun1, Sun-Yran Chang7, Pei-Wen Hsiao8, Dah-Shyong Yu1 and Tai-Lung Cha1,3,4,6,9
1 Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
2 College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, R.O.C.
3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C.
4 Graduate School of Biomedical Science, National Defense Medical Center, Taipei, Taiwan, R.O.C.
5 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
6 Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, R.O.C.
7 Taipei City Hospital, Taipei, Taiwan, R.O.C.
8 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, R.O.C.
9 Department of Immunology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Tai-Lung Cha, email:
Keywords: EZH2, NSC745885, proteasome degradation, G2/M cell-cycle arrest
Received: January 20, 2014 Accepted: March 24, 2014 Published: March 26, 2014
The polycomb group gene, EZH2, is highly expressed in advanced bladder cancer. Here we demonstrated that down-regulation of EZH2 in tumor tissues after neo-adjuvant chemotherapy correlated with good therapeutic response in advanced bladder cancer. We next developed a small molecule, NSC745885, derived from natural anthraquinone emodin, which down-regulated EZH2 via proteasome-mediated degradation. NSC745885 showed potent selective toxicity against multiple cancer cell lines but not normal cells. NSC745885 treatment overcame multiple-drug resistance and inhibited growth of resistant cancer cells. Over-expression of EZH2 in cancer cells attenuated effects of NSC745885, suggesting that down-regulation of EZH2 was responsible for growth inhibition of NSC745885. NSC745885 also suppressed tumor growth and down-regulated EZH2 in vivo. These results indicate that NSC7455889 suppresses bladder cancer by targeting EZH2.
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