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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • CpG Islands / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / metabolism
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • MafG Transcription Factor / metabolism*
  • Mice, Inbred BALB C
  • MutL Protein Homolog 1
  • Mutation
  • Neoplasms, Experimental
  • Nuclear Proteins / genetics*
  • Phenotype
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • CHD8 protein, human
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group Proteins
  • MAFG protein, human
  • MLH1 protein, human
  • MafG Transcription Factor
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1