2. Academic Validation
  3. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

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

  • Nat Commun. 2015 Jan 22;6:6051. doi: 10.1038/ncomms7051.
Daniel Zingg 1,  Julien Debbache 1,  Simon M Schaefer 1,  Eylul Tuncer 1,  Sandra C Frommel 2,  Phil Cheng 3,  Natalia Arenas-Ramirez 4,  Jessica Haeusel 1,  Yudong Zhang 1,  Mario Bonalli 1,  Michael T McCabe 5,  Caretha L Creasy 5,  Mitchell P Levesque 3,  Onur Boyman 4,  Raffaella Santoro 2,  Olga Shakhova 6,  Reinhard Dummer 3,  Lukas Sommer 1
Affiliations

Affiliations

  • 1 Cell and Developmental Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
  • 2 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
  • 3 Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland.
  • 4 Department of Immunology, University Hospital Zurich, Gloriastrasse 30, 8091 Zürich, Switzerland.
  • 5 Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
  • 6 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.
PMID: 25609585 DOI: 10.1038/ncomms7051
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.

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