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J Invest Dermatol. 2015 Jul;135(7):1820-1828. doi: 10.1038/jid.2015.61. Epub 2015 Feb 23.

Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.

Author information

1
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.
2
Departments of Dermatology and Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
3
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
4
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden; Department of Clinical Pathology, Skåne University Hospital, Lund, Sweden.
5
Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
6
Department of Clinical Molecular Biology and Laboratory Sciences, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
7
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.

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.

PMID:
25705847
PMCID:
PMC4720161
DOI:
10.1038/jid.2015.61
[Indexed for MEDLINE]
Free PMC Article

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