title: The BRAF(V600E) causes widespread alterations in gene methylation in the genome of melanoma cells.
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 underexpressed, 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
authors.forename: Dingxie
authors.initials: D
authors.lastname: Liu
authors.forename: Jianli
authors.initials: J
authors.lastname: Dong
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf