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Cancer Cell. 2018 Jul 9;34(1):69-84.e14. doi: 10.1016/j.ccell.2018.06.001. Epub 2018 Jun 28.

EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation.

Author information

1
Stem Cell Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
2
Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Molecular Life Science PhD Program, Life Science Zurich Graduate School, 8057 Zurich, Switzerland.
3
Department of Dermatology, University Hospital Zurich, University of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland.
4
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
5
Stem Cell Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Cancer Biology PhD Program, Life Science Zurich Graduate School, 8057 Zurich, Switzerland.
6
Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, 522 First Avenue, New York, NY 10016, USA.
7
Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
8
Stem Cell Biology, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: lukas.sommer@anatomy.uzh.ch.

Abstract

Human melanomas frequently harbor amplifications of EZH2. However, the contribution of EZH2 to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we show that EZH2 drives tumorigenesis from benign BrafV600E- or NrasQ61K-expressing melanocytes by silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/β-catenin signaling, and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis.

KEYWORDS:

EZH2; PRC2; WNT/β-catenin signaling; epigenetics; melanoma; metastasis; primary cilium; tumor initiation

PMID:
30008323
DOI:
10.1016/j.ccell.2018.06.001
[Indexed for MEDLINE]
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