EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation
Menée à l'aide de modèles murins de mélanome présentant un gène BRAF ou NRAS muté, cette étude met en évidence des mécanismes par lesquels, en induisant la perte des cils primaires des mélanocytes, la protéine EZH2 favorise le processus métastatique
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/?-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.
Cancer Cell 2018