Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase.
Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase.
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染色质重塑因子 LSH 通过抑制富马酸水合酶的活性来驱动癌症进展
DOI：
10.1158/0008-5472.can-16-0268
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Tao Y
中科院分区：
文献类型：
--
作者：
He X;Yan B;Liu S;Jia J;Lai W;Xin X;Tang CE;Luo D;Tan T;Jiang Y;Shi Y;Liu Y;Xiao D;Chen L;Liu S;Mao C;Yin G;Cheng Y;Fan J;Cao Y;Muegge K;Tao Y
染色质修饰是上皮-间质转化（EMT）的关键，EMT赋予癌细胞强大的转移潜力。在这里，我们报告的作用，染色质重塑因子淋巴特异性解旋酶（LSH）在鼻咽癌（NPC），在中国的流行癌症。LSH在NPC中的表达增加，在那里它由EB病毒编码的蛋白LMP 1控制。在体外和体内的NPC细胞中，LSH部分通过调节富马酸水合酶（FH）的表达来促进癌症进展，FH是三羧酸循环的核心成分。LSH与FH启动子结合，募集表观遗传沉默因子G9 a以抑制FH转录。临床上，我们发现鼻咽癌患者血清中TCA中间体的浓度在LSH存在下失调。RNAi介导的FH沉默模拟LSH过表达，建立FH作为LSH效应的下游介质。TCA中间体α-KG和柠檬酸盐部分通过改变IKKα依赖性EMT基因表达增强NPC细胞的恶性特征。以这种方式，LSH通过改变癌细胞代谢以支持EMT来促进NPC的恶性进展。Cancer Res; 76（19）; 5743-55.©2016 AACR.
Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates α-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKα-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT. Cancer Res; 76(19); 5743-55. ©2016 AACR.