title: Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides.
abstract: 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 with 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. Here we studied the possibility that DNA methylation at Notch pathway 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, in particular 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 an epigenetic mechanism regulating the Notch pathway in (MF) that might contribute to the future design of more specific therapeutic strategies.
authors: Servei de Dermatologia, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain; Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Electronic address: FGallardo@parcdesalutmar.cat.
authors: Fernando
authors: F
authors: Gallardo
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain. Electronic address: jsandoval@idibell.cat.
authors: Juan
authors: J
authors: Sandoval
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
authors: Angel
authors: A
authors: Díaz-Lagares
authors: Stem Cells and Cancer Research Laboratory, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Ricard
authors: R
authors: Garcia
authors: Stem Cells and Cancer Research Laboratory, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Teresa
authors: T
authors: D'Altri
authors: Stem Cells and Cancer Research Laboratory, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Jessica
authors: J
authors: González
authors: Servicio de Dermatología, Hospital General de Valencia, Valencia, Spain.
authors: Victor
authors: V
authors: Alegre
authors: Servei de Dermatologia, Hospital de Bellvitge, L'Hospitalet de Llobregat, Spain.
authors: Octavio
authors: O
authors: Servitje
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
authors: Ana-Belén
authors: AB
authors: Crujeiras
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
authors: Ólafur-Andri
authors: ÓA
authors: Stefánsson
authors: Laboratori de Citogenètica, Servei de Patologia. Hospital del Mar, Barcelona, Spain.
authors: Blanca
authors: B
authors: Espinet
authors: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Maria-Inmaculada
authors: MI
authors: Hernández
authors: Biologia Molecular, Servei de Patologia. Hospital del Mar, Barcelona, Spain.
authors: Beatriz
authors: B
authors: Bellosillo
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain; Departament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors: Manel
authors: M
authors: Esteller
authors: Servei de Dermatologia, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain; Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Ramon-Maria
authors: RM
authors: Pujol
authors: Stem Cells and Cancer Research Laboratory, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Electronic address: abigas@imim.es.
authors: Anna
authors: A
authors: Bigas
authors: Stem Cells and Cancer Research Laboratory, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: Lluis
authors: L
authors: Espinosa
mesh_terms: D002135:Calcium-Binding Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D000072100:Jagged-1 Protein; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics*; D008565:Membrane Proteins / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D009182:Mycosis Fungoides / Q000235:genetics*; D051881:Receptor, Notch1 / Q000502:physiology*; D012189:Retrospective Studies; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C509207:MIRN124 microRNA, human; C533896:MIRN200 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins