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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms7051

2041-1723

Daniel Zingg, Julien Debbache, Simon M. Schaefer, Eylül Tuncer, Sandra C. Frommel, Phil F. 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, Lukas Sommer,

Genomics and Chromatin Dynamics

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. The epigenetic modifier EZH2 is highly expressed in melanoma but its role in cancer initiation and progression is still unclear. Here the authors use mouse models and human cell lines to show that EZH2 has an essential role in melanoma progression and metastasis, thus highlighting its potential as a therapeutic target.