Regulation of functional KCNQ1OT1 lncRNA by β-catenin.
Regulation of functional KCNQ1OT1 lncRNA by β-catenin.
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DOI：
10.1038/srep20690
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发表时间：
2016-02-12
影响因子：
4.6
通讯作者：
Kugoh H
中科院分区：
文献类型：
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作者：
Sunamura N;Ohira T;Kataoka M;Inaoka D;Tanabe H;Nakayama Y;Oshimura M;Kugoh H
长非编码 RNA (lncRNA) 通过表观遗传机制参与许多生物过程。我们之前报道过，KCNQ1OT1是人类染色体11p15.5上KCNQ1位点的印迹反义lncRNA，参与印迹KCNQ1簇内的顺式限制沉默。此外，在结直肠癌中频繁观察到 KCNQ1OT1 转录异常。然而，KCNQ1OT1在结直肠癌中转录调控的分子机制和功能作用仍不清楚。在这里，我们发现，在β-连环蛋白在细胞核中过度积累的人结直肠癌细胞中，KCNQ1OT1转录水平显着增加。此外，β-连环蛋白的过度表达导致 KCNQ1OT1 lncRNA 包被区域的增加。另一方面，β-连环蛋白的敲低导致KCNQ1OT1 lncRNA包被的区域显着减少，并且受KCNQ1OT1调节的SLC22A18和PHLDA2基因的mRNA表达增加。我们发现β-连环蛋白可以通过直接结合到KCNQ1OT1启动子来促进KCNQ1OT1转录。我们的证据表明，β-连环蛋白信号传导可能通过直接靶向 KCNQ1OT1 作为一种新型 lncRNA 调节因子，从而促进结直肠癌的发展。
Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role of KCNQ1OT1 in colorectal cancer remain unclear. Here, we show that the KCNQ1OT1 transcriptional level was significantly increased in human colorectal cancer cells in which β-catenin was excessively accumulated in the nucleus. Additionally, overexpression of β-catenin resulted in an increase in KCNQ1OT1 lncRNA-coated territory. On the other hand, knockdown of β-catenin resulted in significant decrease of KCNQ1OT1 lncRNA-coated territory and an increase in the mRNA expression of the SLC22A18 and PHLDA2 genes that are regulated by KCNQ1OT1. We showed that β-catenin can promote KCNQ1OT1 transcription through direct binding to the KCNQ1OT1 promoter. Our evidence indicates that β-catenin signaling may contribute to development of colorectal cancer by functioning as a novel lncRNA regulatory factor via direct targeting of KCNQ1OT1.