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

Author:
  • Martin Lauss
  • Rizwan Haq
  • Helena Cirenajwis
  • Bengt Phung
  • Katja Harbst
  • Johan Staaf
  • Frida Rosengren
  • Karolina Holm
  • Mattias Aine
  • Karin Jirström
  • Åke Borg
  • Christian Busch
  • Jürgen Geisler
  • Per Eystein Lønning
  • Markus Ringnér
  • Jillian Howlin
  • David Fisher
  • Göran B Jönsson
Publishing year: 2015
Language: English
Pages: 1820-1828
Publication/Series: Journal of Investigative Dermatology
Volume: 135
Issue: 7
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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 (TCGA) 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, over-expression 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.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.61.

Keywords

  • Dermatology and Venereal Diseases

Other

Published
  • CREATE Health
  • Melanoma Genomics
  • ISSN: 1523-1747
Åke Borg
Åke Borg
E-mail: ake [dot] borg [at] med [dot] lu [dot] se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

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Professor

Oncology and Pathology, MV

MV 404 C21C2

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