title: Survival of skin cancer stem cells requires the Ezh2 polycomb group protein.
abstract: Polycomb group proteins, including Ezh2, are important candidate stem cell maintenance proteins in epidermal squamous cell carcinoma. We previously showed that epidermal cancer stem cells (ECS cells) represent a minority of cells in tumors, are highly enriched in Ezh2 and drive aggressive tumor formation. We now show that Ezh2 is required for ECS cell survival, migration, invasion and tumor formation and that this is associated with increased histone H3 trimethylation on lysine 27, a mark of Ezh2 action. We also show that Ezh2 knockdown or treatment with Ezh2 inhibitors, GSK126 or EPZ-6438, reduces Ezh2 level and activity, leading to reduced ECS cell spheroid formation, migration, invasion and tumor growth. These studies indicate that epidermal squamous cell carcinoma cells contain a subpopulation of cancer stem (tumor-initiating) cells that are enriched in Ezh2, that Ezh2 is required for optimal ECS cell survival and tumor formation and that treatment with Ezh2 inhibitors may be a strategy for reducing ECS cell survival and suppressing tumor formation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grun
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Sivaprakasam
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine.
authors.forename: Candace
authors.initials: C
authors.lastname: Kerr
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD 21201, USA, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Department of Dermatology, University of Maryland School of Medicine and Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA reckert@umaryland.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D002470:Cell Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016688:Mice, Inbred NOD; D009025:Morpholines; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D001713:Biphenyl Compounds; C577920:GSK-2816126; D007211:Indoles; D009025:Morpholines; D011728:Pyridones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C000593333:tazemetostat