title: Targeting of cancer stem cells by inhibitors of DNA and histone methylation.
abstract: BACKGROUND
  Curative chemotherapy should target cancer stem cells (CSCs). The key characteristics of CSCs are a block in differentiation and an epigenetic signature similar to embryonic stem cells (ESCs). Differentiation by ESCs and CSCs is suppressed by gene silencing through the polycomb repressive complex 2 (PRC2) and/or DNA methylation. PRC2 contains the EZH2 subunit, which catalyzes the trimethylation of histone 3 lysine 27, a gene silencing marker. It is possible to reverse this 'double lock' mechanism using a combination of inhibitors of EZH2 and DNA methylation (5-aza-2'-deoxycytidine), which exhibits remarkable synergistic antineoplastic activity in preclinical studies.
  
  
  METHODS
  The authors discuss several specific EZH2 inhibitors that have been synthesized with antineoplastic activity. One such inhibitor, EPZ-6438 (E7438), has been shown to be effective against lymphoma in a Phase I study. The indirect EZH2 inhibitor, 3-deazaneplanocin-A (DZNep), also exhibits remarkable anticancer activity due to its inhibition of methionine metabolism.
  
  
  CONCLUSIONS
  Agents that target EZH2 warrant Phase I trials. Due to its positive pharmacodynamics, DZNep merits a high priority for clinical investigation. Agents that show positive results in Phase I studies should be advanced to clinical trials for use in combination with 5-aza-2'-deoxycytidine due to the interesting potential of this epigenetic therapy to target CSCs.
authors.affiliation: Université de Montréal, Centre de recherche, Département de Pharmacologie , CHU-Saint-Justine, Montréal, Québec , Canada richard.l.momparler@umontreal.ca.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Momparler
authors.forename: Sylvie
authors.initials: S
authors.lastname: Côté
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D019175:DNA Methylation / Q000187:drug effects; D015195:Drug Design; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing; D006657:Histones / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: 3-deazaneplanocin-A; 5-aza-2’-deoxycytidine; EPZ-6438 (E7438); EZH2 inhibitors; GSK-126; cancer stem cells; decitabine; embryonic stem cells; epigenetic therapy; histone methyltransferase; polycomb repressive complex 2