The BRAF Oncoprotein Functions through the Transcriptional Repressor MAFG to Mediate the CpG Island Methylator Phenotype

被引：183

作者：

Fang, Minggang ^{[1
,2
]}

Ou, Jianhong ^{[2
]}

Hutchinson, Lloyd ^{[3
]}

Green, Michael R. ^{[1
,2
]}

机构：

[1] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA

[2] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA

[3] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA

来源：

MOLECULAR CELL | 2014年 / 55卷 / 06期

关键词：

RECEPTOR TYROSINE KINASE; MICROSATELLITE INSTABILITY; CANCER; GENE; EPIGENETICS; INHIBITOR; ACTIVATION; PROTEINS; MUTATION; PHOSPHORYLATION;

D O I：

10.1016/j.molcel.2014.08.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 micro-satellite 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.

引用

页码：904 / 915

页数：12

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