[PDF][PDF] EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

D Zingg, J Debbache, R Peña-Hernández, AT Antunes… - Cancer cell, 2018 - cell.com
D Zingg, J Debbache, R Peña-Hernández, AT Antunes, SM Schaefer, PF Cheng, D Zimmerli…
Cancer cell, 2018cell.com
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 Braf V600E-or Nras Q61K-
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 …
Summary
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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