The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

Daniel Zingg, Julien Debbache, Simon M. Schaefer, Eylul Tuncer, Sandra C. Frommel, Phil Cheng, Natalia Arenas-Ramirez, Jessica Haeusel, Yudong Zhang, Mario Bonalli, Michael T. McCabe, Caretha L. Creasy, Mitchell P. Levesque, Onur Boyman, Raffaella Santoro, Olga Shakhova, Reinhard Dummer and Lukas Sommer ()
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Daniel Zingg: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Julien Debbache: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Simon M. Schaefer: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Eylul Tuncer: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Sandra C. Frommel: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich
Phil Cheng: University Hospital Zurich
Natalia Arenas-Ramirez: University Hospital Zurich
Jessica Haeusel: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Yudong Zhang: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Mario Bonalli: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Michael T. McCabe: Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Caretha L. Creasy: Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Mitchell P. Levesque: University Hospital Zurich
Onur Boyman: University Hospital Zurich
Raffaella Santoro: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich
Olga Shakhova: Cell and Developmental Biology, Institute of Anatomy, University of Zurich
Reinhard Dummer: University Hospital Zurich
Lukas Sommer: Cell and Developmental Biology, Institute of Anatomy, University of Zurich

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7051

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