Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer
Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer
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长非编码RNA FOXD2-AS1的上调通过EZH2和LSD1表观遗传学沉默EphB3促进癌发生，并预测胃癌的不良预后
DOI：
10.1038/s41388-018-0308-y
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发表时间：
2018-09-06
期刊：
影响因子：
8
通讯作者：
Shu, Yong-qian
中科院分区：
文献类型：
--
作者：
Xu, Tong-peng;Wang, Wen-yu;Shu, Yong-qian
越来越多的数据表明，长非编码RNA(LncRNAs)在生物过程中起着重要的调节作用，在多种肿瘤中都存在调控异常。FOXD2-AS1在胃癌进展中的作用及其相关的生物学机制尚不清楚。综合分析表明，FOXD2-AS1在胃癌中显著上调，并与肿瘤体积大、病理分期晚和预后不良呈正相关。GEO数据集的基因集浓缩分析(GSEA)发现，FOXD2-AS1高表达的患者细胞周期和DNA复制相关基因丰富。FOXD2-AS1功能缺失通过抑制细胞周期抑制胃癌细胞生长，而FOXD2-AS1表达上调促进肿瘤进展。ZAST同源蛋白增强子2(EZH2)和赖氨酸(K)特异性去甲基酶1(LSD1)是FOXD2-AS1的结合伙伴和FOXD2-AS1功能的介导物。机制上，FOXD2-AS1部分通过EZH2和LSD1介导的EphB3下调促进胃癌的发生。结果表明，FOXD2-AS1通过与EZH2和LSD1的直接相互作用，部分通过抑制EphB3在胃癌中发挥肿瘤诱导作用，可能是一种潜在的致癌生物标志物。
Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.