title: Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo.
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.
authors.affiliation: Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Shou-Hung
authors.initials: SH
authors.lastname: Tang
authors.affiliation: College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, R.O.C.
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Hong-Ui
authors.initials: HU
authors.lastname: Wu
authors.affiliation: Graduate School of Biomedical Science, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Yi-Ta
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Mei-Jen
authors.initials: MJ
authors.lastname: Chuang
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.affiliation: Taipei City Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Sun-Yran
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, R.O.C.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Dah-Shyong
authors.initials: DS
authors.lastname: Yu
authors.affiliation: Division of Urology, Department of Surgery, National Defense Medical Center, Taipei, Taiwan, R.O.C. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C. Graduate School of Biomedical Science, National Defense Medical Center, Taipei, Taiwan, R.O.C. Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, R.O.C. Department of Immunology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004351:Drug Resistance / Q000187:drug effects; D004642:Emodin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D046988:Proteasome Endopeptidase Complex; D004642:Emodin