Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma
Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma
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DOI：
10.1073/pnas.1525619113
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发表时间：
2016-02-02
影响因子：
11.1
通讯作者：
Green, Michael R.
中科院分区：
文献类型：
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作者：
Fang, Minggang;Hutchinson, Lloyd;Green, Michael R.
在癌症发展过程中，众所周知，包括肿瘤抑制基因在内的许多基因都被过度甲基化和转录抑制，这种现象被称为表观遗传沉默。一般来说，癌症发展过程中表观遗传沉默所涉及的因素及其机制基础尚不清楚。我们最近描述了一种表观遗传沉默途径，该途径由致癌 B-Raf 原癌基因 (BRAF) 变体 BRAF(V600E) 指导，介导结直肠癌 (CRC) 中广泛的表观遗传沉默。值得注意的是，50-70% 的黑色素瘤中也存在 BRAF(V600E) 突变。在这里，我们表明，我们在 CRC 中发现的相同途径也指导 BRAF 阳性黑色素瘤中一组相似基因的表观遗传沉默。在 CRC 和黑色素瘤中，BRAF (V600E) 通过上调 v-maf 禽类肌肉腱膜纤维肉瘤癌基因同源物 G (MAFG) 促进表观遗传沉默，MAFG 是一种具有序列特异性 DNA 结合活性的转录抑制因子。 MAFG 浓度升高会驱动 DNA 与启动子结合。启动子结合的 MAFG 招募一组辅阻遏物，包括其异二聚体伙伴 BTB 和 CNC 同源 1、碱性亮氨酸拉链转录因子 1 (BACH1)、染色质重塑因子染色质结构域解旋酶 DNA 结合蛋白 8 (CHD8) 和 DNA 甲基转移酶 DNMT3B，从而导致超甲基化和转录沉默。我们的结果揭示了一种常见的 BRAF（V600E）导向的转录调控途径，可介导无关实体瘤中的表观遗传沉默，并为癌蛋白导向的表观遗传沉默的指导性模型提供强有力的支持。
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.