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Mol Cell. 2014 Sep 18;55(6):904-915. doi: 10.1016/j.molcel.2014.08.010. Epub 2014 Sep 11.

The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.

Author information

1
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: michael.green@umassmed.edu.

Abstract

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.

PMID:
25219500
PMCID:
PMC4170521
DOI:
10.1016/j.molcel.2014.08.010
[Indexed for MEDLINE]
Free PMC Article

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