The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
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DOI：
10.1016/j.molcel.2014.08.010
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发表时间：
2014-09-18
期刊：
影响因子：
16
通讯作者：
Green, Michael R.
中科院分区：
文献类型：
--
作者：
Fang, Minggang;Ou, Jianhong;Hutchinson, Lloyd;Green, Michael R.
大多数含有激活的BRAF（BRAF[V600 E]）的结直肠癌（CRC）具有CpG岛甲基化表型（CIMP），其特征是许多基因（包括错配修复基因MLH 1）的异常超甲基化。MLH 1沉默导致微卫星不稳定性和超突变表型。通过RNA干扰筛选，我们确定转录抑制因子MAFG是含BRAF（V600 E）的CRC中MLH 1沉默和CIMP所需的关键因子。在BRAF阳性的人CRC细胞系和肿瘤中，MAFG结合在MLH 1和其他CIMP基因的启动子上，并募集辅阻遏物复合物，包括其异二聚体伴侣BACH 1，染色质重塑因子CHD 8和DNA甲基转移酶DNMT 3B，导致超甲基化和转录沉默。BRAF（V600 E）增加BRAF/MEK/ERK信号传导，导致磷酸化和MAFG水平升高，从而驱动DNA结合。对KRAS阳性CRC中转录沉默的CIMP基因的分析表明，不同的癌蛋白指导不同阻遏物复合物在共同启动子上的组装。
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 RNA interference 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.
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