LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation.
LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation.
复制标题
LincRNA FEZF1-AS1 通过 LSD1 介导的 H3K4me2 去甲基化抑制 p21 表达促进胃癌增殖
DOI：
10.1186/s12943-017-0588-9
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发表时间：
2017-02-16
期刊：
影响因子：
37.3
通讯作者：
Ji G
中科院分区：
文献类型：
--
作者：
Liu YW;Xia R;Lu K;Xie M;Yang F;Sun M;De W;Wang C;Ji G
虽然胃癌患者的预后有良好的进展，但仍有一些患者具有不寻常的局部和全身复发模式。因此，需要更好地了解疾病的早期分子事件。目前的研究表明，长链非编码RNA（lncRNA）可能是参与胃癌发生发展的一类重要的功能调节因子。我们以前的研究表明HOTAIR参与胃癌的发生，HOTAIR的过表达预示着不良的预后。本研究旨在探讨LncRNA FEZF 1-AS 1在胃癌中的表达特点。采用QRT-PCR方法检测FEZF 1-AS 1在胃癌组织和细胞中的表达。采用MTT法、克隆形成实验和裸鼠移植瘤模型检测FEZF 1-AS 1的体内外致瘤作用。通过生物信息学分析筛选FEZF 1-AS 1下游靶基因。通过细胞周期分析、ChIP、RIP、RNA Pulldown等方法探讨其分子机制。在本研究中，我们报道了FEZF 1-AS 1，一个2564 bp的RNA，在胃癌中过表达，并且FEZF 1-AS 1表达上调表明肿瘤更大和更高的临床分期;另外，FEZF 1-AS 1的更高表达预示预后不良。进一步的实验表明，FEZF 1-AS 1基因敲减可显著抑制胃癌细胞的增殖，并诱导G1期阻滞和凋亡，而内源性表达FEZF 1-AS 1则促进胃癌细胞的生长。RIP和RNA-pulldown实验表明，FEZF 1-AS 1通过与最早发现的去甲基化酶LSD 1结合，抑制P21的表达。ChIP实验表明LSD 1可直接与P21启动子结合，诱导H3 K4 me 2去甲基化。综上所述，FEZF 1-AS 1可能通过抑制P21表达而成为胃癌的“癌基因”，FEZF 1-AS 1可能成为胃癌患者的候选预后生物标志物和新的治疗靶点。本文的在线版本（doi：10.1186/s12943-017-0588-9）包含补充材料，可供授权用户使用。
Although the prognosis of gastric cancer patients have a favorable progression, there are some patients with unusual patterns of locoregional and systemic recurrence. Therefore, a better understanding of early molecular events of the disease is needed. Current evidences demonstrate that long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. Our previous studies suggest that HOTAIR contributes to gastric cancer development, and the overexpression of HOTAIR predicts a poor prognosis. In this study, we investigated the characteristic of the LncRNA FEZF1-AS1 in gastric cancer. QRT-PCR was used to detect the expression of FEZF1-AS1 in gastric cancer tissues and cells. MTT assays, clonogenic survival assays and nude mouse xenograft model were used to examine the tumorigenesis function of FEZF1-AS1 in vitro and in vivo. Bioinformatics analysis were used to select downstream target genes of FEZF1-AS1. Cell cycle analysis, ChIP, RIP,RNA Pulldown assays were examined to dissect molecular mechanisms. In this study, we reported that FEZF1-AS1, a 2564 bp RNA, was overexpressed in gastric cancer, and upregulated FEZF1-AS1 expression indicated larger tumor size and higher clinical stage; additional higher expression of FEZF1-AS1 predicted poor prognosis. Further experiments revealed that knockdown FEZF1-AS1 significantly inhibited gastric cancer cells proliferation by inducing G1 arrest and apoptosis, whereas endogenous expression FEZF1-AS1 promoted cell growth. Additionally, RIP assay and RNA-pulldown assay evidenced that FEZF1-AS1 could epigenetically repress the expression of P21 via binding with LSD1, the first discovered demethylase. ChIP assays demonstrated that LSD1 could directly bind to the promoter of P21, inducing H3K4me2 demethylation. In summary, these data demonstrated that FEZF1-AS1 could act as an “oncogene” for gastric cancer partly through suppressing P21 expression; FEZF1-AS1 may be served as a candidate prognostic biomarker and target for new therapies of gastric cancer patients. The online version of this article (doi:10.1186/s12943-017-0588-9) contains supplementary material, which is available to authorized users.