title: Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker.
abstract: The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side-effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real-time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non-small-cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD-18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor-specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow-up in some lung cancer patients after surgical treatment.
authors.affiliation: Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takawa
authors.forename: Ken
authors.initials: K
authors.lastname: Masuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Kunizaki
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takagi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwai
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamane
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maejima
authors.forename: Helen I
authors.initials: HI
authors.lastname: Field
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akasu
authors.forename: Masanori
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Eijyu
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Atomi
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D063151:Polycomb Repressive Complex 2; D011379:Prognosis; D016016:Proportional Hazards Models; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2