title: Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells.
abstract: Colorectal cancer is among the leading causes of cancer death in the USA. The polycomb repressive complex 2 (PRC2), including core components SUZ12 and EZH2, represents a key epigenetic regulator of digestive epithelial cell physiology and was previously shown to promote deleterious effects in a number of human cancers, including colon. Using colon cancer stem cells (CCSC) isolated from human primary colorectal tumors, we demonstrate that SUZ12 knockdown and treatment with DZNep, one of the most potent EZH2 inhibitors, increase apoptosis levels, marked by decreased Akt phosphorylation, in CCSCs, while embryonic stem (ES) cell survival is not affected. Moreover, DZNep treatments lead to increased PTEN expression in these highly tumorigenic cells. Taken together, our findings suggest that pharmacological inhibition of PRC2 histone methyltransferase activity may constitute a new, epigenetic therapeutic strategy to target highly tumorigenic and metastatic colon cancer stem cells.
authors.affiliation: Pharmacology Department, Weill Cornell Medical College, NY 10065, USA. yannick.benoit@usherbrooke.ca
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Benoit
authors.forename: Mavee S
authors.initials: MS
authors.lastname: Witherspoon
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Laursen
authors.forename: Amel
authors.initials: A
authors.lastname: Guezguez
authors.forename: Marco
authors.initials: M
authors.lastname: Beauséjour
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Beaulieu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D044127:Epigenesis, Genetic; D019084:Fluorescent Antibody Technique, Indirect; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D009363:Neoplasm Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human