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Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2 LSD1 in colorectal cancer

机译:长非编码RNA HOXA-AS2通过与EZH2LSD1结合抑制结直肠癌中的P21和KLF2表达转录

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摘要

Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer (CRC) are not known. Here, we identified that HOXA-AS2 is significantly upregulated in CRC tissue. In addition, increased HOXA-AS2 expression is associated with a larger tumor size and an advanced pathological stage in CRC patients. HOXA-AS2 knockdown significantly suppressed proliferation by blocking the G1/S transition and caused apoptosis of CRC cells in vitro and in vivo. The mechanistic investigations showed that HOXA-AS2 could interact with EZH2 (enhancer of zeste homolog 2), LSD1 (lysine specific demethylase 1) and recruit them to p21 (CDKN1A), KLF2 promoter regions to repress their transcription. Furthermore, the rescue experiments demonstrated that HOXA-AS2 oncogenic function is partly through regulating p21. In conclusion, our data suggest that HOXA-AS2 may function as an oncogene by modulating the multiple genes expression involved in CRC proliferation, and also provides a potential target for CRC therapy.
机译:长的非编码RNA(lncRNA)作为涉及人类致癌作用的一类新的功能调节剂已受到越来越多的关注。 HOXA簇反义RNA 2(HOXA-AS2)是位于HOXA簇中HOXA3和HOXA4基因之间的1048 bp lncRNA,可在转录水平上调节基因表达。以前发现HOXA-AS2在胃癌(GC)中过表达,并促进GC细胞增殖。然而,其在结直肠癌(CRC)中的潜在作用和分子机制尚不清楚。在这里,我们确定了HOXA-AS2在CRC组织中显着上调。此外,CRC患者中HOXA-AS2表达的增加与更大的肿瘤大小和晚期病理分期有关。 HOXA-AS2敲低通过阻止G1 / S过渡来显着抑制增殖,并在体外和体内引起CRC细胞凋亡。机理研究表明,HOXA-AS2可以与EZH2(zeste同源物2的增强子),LSD1(赖氨酸特异性脱甲基酶1)相互作用并将它们募集到p21(CDKN1A),KLF2启动子区域来抑制其转录。此外,救援实验表明HOXA-AS2致癌功能部分是通过调节p21。总之,我们的数据表明HOXA-AS2可能通过调节参与CRC增殖的多个基因表达而充当癌基因,并且还为CRC治疗提供了潜在的靶标。

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