A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy
A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy
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DOI：
10.1038/s41388-018-0369-y
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发表时间：
2018-11-01
期刊：
影响因子：
8
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
--
作者：
Du, William W.;Yang, Weining;Yang, Burton B.
环状RNA是一类在哺乳动物细胞中广泛表达的非编码RNA。全基因组分析揭示了跨物种的丰富的和进化上保守的环状RNA，这表明这些物种的特定生理作用。使用微阵列方法，我们检测到在8个乳腺癌细胞系和乳腺癌患者中环状RNA circ-Dnmt 1的表达增加。沉默circ-Dnmt 1抑制细胞增殖和存活。异位circ-Dnmt 1通过刺激细胞自噬增加乳腺癌细胞的增殖和存活能力。我们发现circ-Dnmt 1介导的自噬在抑制细胞衰老和增加肿瘤异种移植物生长方面是必不可少的。我们进一步发现，异位表达的circ-Dnmt 1可以与p53和AUF 1相互作用，促进两种蛋白质的核转位。p53核转位诱导细胞自噬，而AUF 1核转位降低Dnmt 1 mRNA的不稳定性，导致Dnmt 1翻译增加。从这里，功能性Dnmt 1可以转移到细胞核中，抑制p53转录。计算算法显示，p53和AUF 1都可以与circ-Dnmt 1 RNA的不同区域结合。我们的研究结果表明，高表达的环状RNA circ-Dnmt 1可以结合并调节乳腺癌细胞中的致癌蛋白。因此，circ-Dnmt 1似乎是一种致癌环状RNA，具有进一步临床前研究的潜力。
Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research.