LncRNA-mediated regulation of SOX9 expression in basal subtype breast cancer cells
LncRNA-mediated regulation of SOX9 expression in basal subtype breast cancer cells
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DOI：
10.1261/rna.073254.119
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发表时间：
2020-02-01
期刊：
影响因子：
4.5
通讯作者：
Prasanth, Kannanganattu V.
中科院分区：
文献类型：
--
作者：
Tariq, Aamira;Hao, Qinyu;Prasanth, Kannanganattu V.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌（BC）亚型之一，预后差，复发率高。最近的研究已经确定了几个lncRNA（长链非编码RNA）在BC病理生物学中发挥的重要作用。lncRNA的细胞类型特异性表达及其在调节致癌基因和抑癌基因表达中的潜在作用使其成为有前途的癌症药物靶点。通过在等基因TNBC/基础亚型BC进展细胞系模型中进行转录组筛选，我们最近报道了在乳腺癌进展期间显示异常表达的类似1800个lncRNA。对一种这样的核保留lncRNA linc 02095的机制研究表明，它通过促进致癌转录因子SOX 9的表达来促进乳腺癌增殖。linc 02095和SOX 9在BC患者中以及在基底亚型BC细胞系中显示共调节表达。linc 02095的敲低导致BC细胞增殖降低，而其过表达促进细胞增殖。Linc 02095-耗尽的细胞显示S 0X 9表达减少，伴随着S 0X 9基因体处RNA聚合酶II占据减少以及S 0X 9 mRNA输出缺陷，这意味着Linc 02095正调控S 0X 9转录和mRNA输出。最后，我们确定了BC细胞中控制linc 02095和SOX 9表达的正反馈回路。因此，我们的研究结果揭示了核lncRNA linc 02095通过促进BC中关键致癌转录因子的表达而具有促肿瘤活性。
Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer (BC) subtypes with a poor prognosis and high recurrence rate. Recent studies have identified vital roles played by several lncRNAs (long noncoding RNAs) in BC pathobiology. Cell type-specific expression of lncRNAs and their potential role in regulating the expression of oncogenic and tumor suppressor genes have made them promising cancer drug targets. By performing a transcriptome screen in an isogenic TNBC/basal subtype BC progression cell line model, we recently reported similar to 1800 lncRNAs that display aberrant expression during breast cancer progression. Mechanistic studies on one such nuclear-retained lncRNA, linc02095, reveal that it promotes breast cancer proliferation by facilitating the expression of oncogenic transcription factor, SOX9. Both linc02095 and SOX9 display coregulated expression in BC patients as well in basal subtype BC cell lines. Knockdown of linc02095 results in decreased BC cell proliferation, whereas its overexpression promotes cells proliferation. Linc02095-depleted cells display reduced expression of SOX9 concomitant with reduced RNA polymerase II occupancy at the SOX9 gene body as well as defective SOX9 mRNA export, implying that linc02095 positively regulates SOX9 transcription and mRNA export. Finally, we identify a positive feedback loop in BC cells that controls the expression of both linc02095 and SOX9. Thus, our results unearth tumor-promoting activities of a nuclear lncRNA linc02095 by facilitating the expression of key oncogenic transcription factor in BC.