title: Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma.
abstract: During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. In general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. We have recently described an epigenetic silencing pathway, directed by the oncogenic B-Raf proto-oncogene (BRAF) variant BRAF(V600E), that mediates widespread epigenetic silencing in colorectal cancer (CRC). Notably, the BRAF(V600E) mutation is also present in 50-70% of melanomas. Here, we show that the same pathway we identified in CRC also directs epigenetic silencing of a similar set of genes in BRAF-positive melanoma. In both CRC and melanoma, BRAF(V600E) promotes epigenetic silencing through up-regulation of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), a transcriptional repressor with sequence-specific DNA-binding activity. The elevated concentration of MAFG drives DNA binding on the promoter. Promoter-bound MAFG recruits a set of corepressors that includes its heterodimeric partner BTB and CNC homology 1, basic leucine zipper transcription factor 1 (BACH1), the chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8), and the DNA methyltransferase DNMT3B, resulting in hypermethylation and transcriptional silencing. Our results reveal a common BRAF(V600E)-directed transcriptional regulatory pathway that mediates epigenetic silencing in unrelated solid tumors and provide strong support for an instructive model of oncoprotein-directed epigenetic silencing.
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Minggang
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Hutchinson
authors.affiliation: Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: April
authors.initials: A
authors.lastname: Deng
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; michael.green@umassmed.edu.
authors.forename: Michael R
authors.identifier: http://orcid.org/0000-0003-3017-3298
authors.initials: MR
authors.lastname: Green
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D051259:MafG Transcription Factor / Q000502:physiology*; D008545:Melanoma / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C103944:MAFG protein, human; C000715470:MAS1 protein, human; D051259:MafG Transcription Factor; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF(V600E); MAFG; colorectal cancer; epigenetic silencing; melanoma