title: Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.
abstract: The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways, although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes, and dermal fibroblasts and utilized The Cancer Genome Atlas data for experimental validation. By integrating DNA methylation and gene expression data, we found that hypermethylation of MITF and its co-regulated differentiation pathway genes corresponded to decreased gene expression levels. In cell lines with a hypermethylated MITF-pathway, overexpression of MITF did not alter the expression level or methylation status of the MITF pathway genes. In contrast, however, demethylation treatment of these cell lines induced MITF-pathway activity, confirming that gene regulation was controlled via methylation. The discovery that the activity of the master regulator of pigmentation, MITF, and its downstream targets may be regulated by hypermethylation has significant implications for understanding the development and evolvement of melanoma.
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Departments of Dermatology and Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirenajwis
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Phung
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Harbst
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Rosengren
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Holm
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Aine
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; Department of Clinical Pathology, Skåne University Hospital, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Sciences, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.affiliation: Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Jillian
authors.initials: J
authors.lastname: Howlin
authors.affiliation: Departments of Dermatology and Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: Goran_B.Jonsson@med.lu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D018709:Statistics, Nonparametric; D015534:Trans-Activators
chemical_list: C409062:CXXC1 protein, human; D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; D015534:Trans-Activators