The BRAF V600E causes widespread alterations in gene methylation in the genome of melanoma cells

Peng Hou, Dingxie Liu, Jianli Dong, Mingzhao Xing

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Although BRAF V600E is well known to play an important role in the tumorigenesis of melanoma, its molecular mechanism, particularly the epigenetic aspect, has been incompletely understood. Here, we investigated the role of BRAF V600E signaling in altering gene methylation in the genome of melanoma cells using a methylated CpG island amplification/ CpG island microarray system and searched for genes coupled to the BRAF V600E signaling through methylation aberrations. The results indicated that a wide range of genes with broad functions were linked to BRAF V600E signaling through their hyper- or hypomethylation. Expression of 59 genes hypermethylated upon BRAF knockdown was selectively tested and found to be largely correspondingly under-expressed, suggesting that these genes were naturally hypomethylated and overexpressed with BRAF V600E in melanoma. This BRAF V600E-promoted hypomethylation was confirmed on genes selectively examined in primary melanoma tumors. Some of these genes were functionally tested and demonstrated to play a role in melanoma cell proliferation and invasion. As a mechanism of aberrant gene methylation driven by BRAF V600E, expression of the DNA methyltransferase 1 and histone methyltransferase EZH2 was profoundly affected by BRAF V600E. We have thus uncovered a previously unrecognized prominent epigenetic mechanism in the tumorigenesis of melanoma driven by BRAF V600E. Many of the functionally important genes controlled by the BRAF V600E signaling through aberrant methylation may prove to be novel therapeutic targets for melanoma.

Original languageEnglish (US)
Pages (from-to)286-295
Number of pages10
JournalCell Cycle
Volume11
Issue number2
DOIs
StatePublished - Jan 15 2012

Fingerprint

Methylation
Melanoma
Genome
Genes
CpG Islands
Epigenomics
Carcinogenesis
Methyltransferases
Cell Proliferation
Gene Expression
DNA
Neoplasms

Keywords

  • BRAF mutation
  • DNA methylation
  • Gene hypermethylation
  • Gene hypomethylation
  • MAP kinase pathway
  • Melanoma

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

The BRAF V600E causes widespread alterations in gene methylation in the genome of melanoma cells. / Hou, Peng; Liu, Dingxie; Dong, Jianli; Xing, Mingzhao.

In: Cell Cycle, Vol. 11, No. 2, 15.01.2012, p. 286-295.

Research output: Contribution to journalArticle

Hou, Peng ; Liu, Dingxie ; Dong, Jianli ; Xing, Mingzhao. / The BRAF V600E causes widespread alterations in gene methylation in the genome of melanoma cells. In: Cell Cycle. 2012 ; Vol. 11, No. 2. pp. 286-295.
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