Pharmacologic down-regulation of EZH2 suppresses bladder cancerin vitroandin vivo

// Shou-Hung Tang 1 , Hsu-Shan Huang 2 , Hong-Ui Wu 3 , Yi-Ta Tsai 4 , Mei-Jen Chuang 1 , Cheng-Ping Yu 5 , Shih-Ming Huang 6 , Guang-Huan Sun 1 , Sun-Yran Chang 7 , Pei-Wen Hsiao 8 , Dah-Shyong Yu 1 and Tai-Lung Cha 1,3,4,6,9 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. Correspondence: 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 Abstract 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.