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

Lauss, Martin LU ; Haq, Rizwan; Cirenajwis, Helena LU ; Phung, Bengt LU ; Harbst, Katja LU ; Staaf, Johan LU ; Rosengren, Frida LU ; Holm, Karolina LU ; Aine, Mattias LU and Jirström, Karin LU , et al. (2015) In Journal of Investigative Dermatology 135(7). p.1820-1828
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 (TCGA) data for experimental validation. By integrating DNA methylation and gene expression data we found that hypermethylation of MITF and its co-regulated differentiation... (More)
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. (Less)
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Journal of Investigative Dermatology
volume
135
issue
7
pages
1820 - 1828
publisher
Nature Publishing Group
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  • pmid:25705847
  • wos:000356180100021
  • scopus:84931572348
ISSN
1523-1747
DOI
10.1038/jid.2015.61
project
CREATE Health
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English
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yes
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e0e6fe77-7feb-44f8-9ffa-26766d9fe293 (old id 5143083)
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http://www.ncbi.nlm.nih.gov/pubmed/25705847?dopt=Abstract
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2015-03-10 19:21:52
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2017-11-19 03:24:42
@article{e0e6fe77-7feb-44f8-9ffa-26766d9fe293,
  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 (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.},
  author       = {Lauss, Martin and Haq, Rizwan and Cirenajwis, Helena and Phung, Bengt and Harbst, Katja and Staaf, Johan and Rosengren, Frida and Holm, Karolina and Aine, Mattias and Jirström, Karin and Borg, Åke and Busch, Christian and Geisler, Jürgen and Eystein Lønning, Per and Ringnér, Markus and Howlin, Jillian and Fisher, David and Jönsson, Göran B},
  issn         = {1523-1747},
  language     = {eng},
  number       = {7},
  pages        = {1820--1828},
  publisher    = {Nature Publishing Group},
  series       = {Journal of Investigative Dermatology},
  title        = {Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.},
  url          = {http://dx.doi.org/10.1038/jid.2015.61},
  volume       = {135},
  year         = {2015},
}