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

Author

Listed:
  • 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
    University Hospital Zurich)

  • Reinhard Dummer

    (University Hospital Zurich)

  • Lukas Sommer

    (Cell and Developmental Biology, Institute of Anatomy, University of Zurich)

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.

Suggested Citation

  • 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 & Caret, 2015. "The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors," Nature Communications, Nature, vol. 6(1), pages 1-17, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7051
    DOI: 10.1038/ncomms7051
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    Cited by:

    1. Rui Liu & Zongwei Li & Rui Chen & Zhihong Fang & Zhiqiang Liu & Huan Liu, 2025. "EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

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