MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy.
MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy.
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DOI：
10.1158/2159-8290.cd-15-0341
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发表时间：
2016-01
期刊：
影响因子：
28.2
通讯作者：
Silver DP
中科院分区：
文献类型：
--
作者：
Neupane M;Clark AP;Landini S;Birkbak NJ;Eklund AC;Lim E;Culhane AC;Barry WT;Schumacher SE;Beroukhim R;Szallasi Z;Vidal M;Hill DE;Silver DP
一个无偏见的基因组规模筛选未突变的基因，驱动癌症生长时，过度表达确定MECP 2作为一种新的致癌基因。MECP 2位于X染色体的一个区域，该区域在18%的癌症中显著扩增，许多癌细胞系扩增、过表达MECP 2，并且依赖于MECP 2表达来生长。在几种癌症类型中，MECP 2拷贝数增加和RAS家族成员改变是相互排斥的。MECP 2剪接亚型激活由激活的RAS靶向的主要生长因子途径，MAPK和PI 3 K途径。在KRAS下调后，MECP 2挽救了KRASG 12 C成瘾细胞系的生长，并且在MECP 2下调后，激活的KRAS挽救了MECP 2成瘾细胞系的生长。MECP 2与表观遗传修饰5-羟甲基胞嘧啶的结合是有效转化所需的。这些观察结果表明，MECP 2是一种常见的扩增癌基因，具有不寻常的表观遗传作用模式。
An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified MECP2 as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS down-regulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.