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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylmethionine Decarboxylase / metabolism
  • Animals
  • Cell Proliferation
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genotype
  • Homeostasis
  • Humans
  • Melanocytes / metabolism
  • Melanoma / metabolism*
  • Melanoma, Experimental / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / physiology*
  • Skin Neoplasms / metabolism*
  • Treatment Outcome

Substances

  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • Adenosylmethionine Decarboxylase

Supplementary concepts

  • Melanoma, Cutaneous Malignant