title: The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors.
abstract: Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zingg
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Debbache
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Schaefer
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Eylul
authors.initials: E
authors.lastname: Tuncer
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Frommel
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors.forename: Phil
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Immunology, University Hospital Zurich, Gloriastrasse 30, 8091 Zürich, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Arenas-Ramirez
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Haeusel
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Bonalli
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Caretha L
authors.initials: CL
authors.lastname: Creasy
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Immunology, University Hospital Zurich, Gloriastrasse 30, 8091 Zürich, Switzerland.
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Santoro
authors.affiliation: 1] Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland [2] Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zürich, Switzerland.
authors.forename: Olga
authors.initials: O
authors.lastname: Shakhova
authors.affiliation: Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism*; D016896:Treatment Outcome; D000096142:Cutaneous Malignant Melanoma
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D012437:Adenosylmethionine Decarboxylase