The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
Most colorectal cancers (CRCs) containing activated BRAF (BRAF[V600E]) have a CpG island methylator phenotype (CIMP) characterized by aberrant hypermethylation of many genes, including the mismatch repair gene MLH1. MLH1 silencing results in microsatellite instability and a hypermutable phenotype. Through an RNAi screen, here we identify the transcriptional repressor MAFG as ... the pivotal factor required for MLH1 silencing and CIMP in CRCs containing BRAF(V600E). In BRAF-positive human CRC cell lines and tumors, MAFG is bound at the promoters of MLH1 and other CIMP genes, and recruits a corepressor complex that includes its heterodimeric partner BACH1, the chromatin remodeling factor CHD8, and the DNA methyltransferase DNMT3B, resulting in hypermethylation and transcriptional silencing. BRAF(V600E) increases BRAF/MEK/ERK signaling resulting in phosphorylation and elevated levels of MAFG, which drives DNA binding. Analysis of transcriptionally silenced CIMP genes in KRAS-positive CRCs indicates that different oncoproteins direct the assembly of distinct repressor complexes on common promoters.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Basic-Leucine Zipper Transcription Factors, Cell Line, Tumor, Colorectal Neoplasms, CpG Islands, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA-Binding Proteins, Fanconi Anemia Complementation Group Proteins, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, MafG Transcription Factor, Mice, Inbred BALB C, MutL Protein Homolog 1, Mutation, Neoplasms, Experimental, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf, Repressor Proteins, Signal Transduction, Transcription Factors
Adaptor Proteins, Signal Transducing, Animals, Basic-Leucine Zipper Transcription Factors, Cell Line, Tumor, Colorectal Neoplasms, CpG Islands, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA-Binding Proteins, Fanconi Anemia Complementation Group Proteins, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, MafG Transcription Factor, Mice, Inbred BALB C, MutL Protein Homolog 1, Mutation, Neoplasms, Experimental, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf, Repressor Proteins, Signal Transduction, Transcription Factors
Mol. Cell
Date: Sep. 18, 2014
PubMed ID: 25219500
View in: Pubmed Google Scholar
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