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


Zingg, Daniel; Debbache, Julien; Schaefer, Simon M; Tuncer, Eylul; Frommel, Sandra C; Cheng, Phil; Arenas-Ramirez, Natalia; Haeusel, Jessica; Zhang, Yudong; Bonalli, Mario; McCabe, Michael T; Creasy, Caretha L; Levesque, Mitchell P; Boyman, Onur; Santoro, Raffaella; Shakhova, Olga; Dummer, Reinhard; Sommer, Lukas (2015). The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nature Communications, 6:6051.

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.

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
05 Vetsuisse Faculty > Institute of Veterinary Biochemistry and Molecular Biology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:22 January 2015
Deposited On:12 Mar 2015 14:07
Last Modified:27 Aug 2016 07:45
Publisher:Nature Publishing Group
ISSN:2041-1723
Publisher DOI:https://doi.org/10.1038/ncomms7051
PubMed ID:25609585
Permanent URL: https://doi.org/10.5167/uzh-109536

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