title: The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane.
abstract: Melanoma is a metastatic cancer associated with poor survival. Here, we study a subpopulation of melanoma cancer cells displaying melanoma cancer stem cell (MCS cells) properties including elevated expression of stem cell markers, increased ability to survive as spheroids, and enhanced cell migration and invasion. We show that the Ezh2 stem cell survival protein is enriched in MCS cells and that Ezh2 knockdown or treatment with small molecule Ezh2 inhibitors, GSK126 or EPZ-6438, reduces Ezh2 activity. This reduction is associated with a reduced MCS cell spheroid formation, migration, and invasion. Moreover, the diet-derived cancer prevention agent, sulforaphane (SFN), suppresses MCS cell survival and this is associated with loss of Ezh2. Forced expression of Ezh2 partially reverses SFN suppression of MCS cell spheroid formation, migration, and invasion. A375 melanoma cell-derived MCS cells form rapidly growing tumors in immune-compromised mice and SFN treatment of these tumors reduces tumor growth and this is associated with reduced Ezh2 level and H3K27me3 formation, reduced matrix metalloproteinase expression, increased TIMP3 expression and increased apoptosis. These studies identify Ezh2 as a MCS cell marker and cancer stem cell prevention target, and suggest that SFN acts to reduce melanoma tumor formation via a mechanism that includes suppression of Ezh2 function. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Fisher
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Gautam
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Dan
authors.initials: D
authors.lastname: Grun
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D017879:Isothiocyanates / Q000627:therapeutic use*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013454:Sulfoxides; D015854:Up-Regulation
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C016766:sulforaphane
keywords: Ezh2; cancer; cancer prevention; cancer therapy; epigenetic; melanoma; polycomb; stem cell; sulforaphane