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EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation


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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > Cell Biology
Life Sciences > Cancer Research
Uncontrolled Keywords:EZH2; PRC2; WNT/β-catenin signaling; epigenetics; melanoma; metastasis; primary cilium; tumor initiation
Language:English
Date:28 June 2018
Deposited On:19 Aug 2018 12:46
Last Modified:11 Aug 2020 08:24
Publisher:Cell Press (Elsevier)
ISSN:1535-6108
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ccell.2018.06.001
PubMed ID:30008323
Project Information:
  • : FunderSNSF
  • : Grant IDCRSII3_154412
  • : Project TitleGrowing or Going: Mechanisms Underlying Tumor Progression in Melanoma
  • : FunderSNSF
  • : Grant ID31003A_173056
  • : Project TitleAnalysis of nucleolus and nucleolar chromatin factors in the regulation of stem cells
  • : FunderSNSF
  • : Grant ID31003A_169859
  • : Project TitleNeural Crest Stem Cells and Melanoma Formation: a common theme

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