1. An actionable axis linking NFATc2 to EZH2 controls the EMT-like program of melanoma cells
- Author
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Roberta Mortarini, Fabio Benigni, Mario Santinami, Paola Baldassari, Alessandra Molla, Gabriella Nicolini, Ilaria Bersani, Andrea Maurichi, Andrea Anichini, Valentina Perotti, and Giulia Grazia
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Down-Regulation ,Apoptosis ,Mice, SCID ,macromolecular substances ,Biology ,Article ,GTP Phosphohydrolases ,Targeted therapy ,Proto-Oncogene Proteins c-myc ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Gene silencing ,Enhancer of Zeste Homolog 2 Protein ,Gene Silencing ,Melanoma ,neoplasms ,Molecular Biology ,Cell Proliferation ,Regulation of gene expression ,NFATC Transcription Factors ,Forkhead Box Protein M1 ,EZH2 ,medicine.disease ,Microphthalmia-associated transcription factor ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,FOXM1 ,Female - Abstract
Discovery of new actionable targets and functional networks in melanoma is an urgent need as only a fraction of metastatic patients achieves durable clinical benefit by targeted therapy or immunotherapy approaches. Here we show that NFATc2 expression is associated with an EMT-like transcriptional program and with an invasive melanoma phenotype, as shown by analysis of melanoma cell lines at the mRNA and protein levels, interrogation of the TCGA melanoma dataset and characterization of melanoma lesions by immunohistochemistry. Gene silencing or pharmacological inhibition of NFATc2 downregulated EMT-related genes and AXL, and suppressed c-Myc, FOXM1, and EZH2. Targeting of c-Myc suppressed FOXM1 and EZH2, while targeting of FOXM1 suppressed EZH2. Inhibition of c-Myc, or FOXM1, or EZH2 downregulated EMT-related gene expression, upregulated MITF and suppressed migratory and invasive activity of neoplastic cells. Stable silencing of NFATc2 impaired melanoma cell proliferation in vitro and tumor growth in vivo in SCID mice. In NFATc2+ EZH2+ melanoma cell lines pharmacological co-targeting of NFATc2 and EZH2 exerted strong anti-proliferative and pro-apoptotic activity, irrespective of BRAF or NRAS mutations and of BRAF inhibitor resistance. These results provide preclinical evidence for a role of NFATc2 in shaping the EMT-like melanoma phenotype and reveal a targetable vulnerability associated with NFATc2 and EZH2 expression in melanoma cells belonging to different mutational subsets.
- Published
- 2019