Elsevier, Journal of Investigative Dermatology, 12(135), p. 3144-3152
DOI: 10.1038/jid.2015.328
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Notch is a family of transmembrane receptors that participate in the regulation of cell differentiation, proliferation and stemness. Notch pathway activation has also been found associated to different human cancers including primary cutaneous T-cell lymphomas (CTCL). The elucidation of the mechanisms driving Notch activation in these particular diseases has remained elusive. We here studied the possibility that DNA methylation at Notch pathways gene promoters, and/or deregulation of Notch-associated microRNAs contribute to activate Notch in Mycosis Fungoides (MF). By genome-wide DNA methylation analysis, we failed to detect any consistent methylation at the Notch1, the Notch-ligand Jagged1 or the Notch-target Hes1 gene promoters, but found a significant methylation of the Notch-related microRNAs, particularly miR-200c and miR-124. Downregulation of miR-200c is associated with overexpression of Jagged1, concomitant to Notch1 activation. CTCL cell lines were infected with lentiviral vector encoding for miR-200c and, ectopic expression of miR-200c in CTCL lines resulted in Jagged1 protein downregulation associated with a reduction in the levels of active Notch1. Our study deciphers a epigenetic mechanism regulating Notch pathway in MF that might contribute to the future design of more specific therapeutic strategies.Journal of Investigative Dermatology accepted article preview online, 24 August 2015. doi:10.1038/jid.2015.328.