Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity
Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity
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DOI：
10.1038/cdd.2016.133
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发表时间：
2017-02-01
影响因子：
12.4
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
--
作者：
Du, William W.;Fang, Ling;Yang, Burton B.
环状rna是一类受到广泛关注的非编码rna。尽管有报道显示环状rna充当microRNA海绵，但环状rna的生物学功能在很大程度上仍然未知。我们发现，在患者肿瘤样本和一组癌细胞中，circ-Foxo3的表达最低。有趣的是，在癌细胞凋亡过程中，circ-Foxo3的表达显著增加。我们发现，沉默内源性circ-Foxo3可提高细胞活力，而circ-Foxo3的异位表达可触发应激诱导的细胞凋亡并抑制肿瘤异种移植物的生长。此外，circ-Foxo3的表达增加了Foxo3蛋白水平，但抑制了p53水平。通过与两者结合，circ-Foxo3促进了mdm2诱导的p53泛素化和随后的降解，导致p53整体下降。由于circ-Foxo3与Foxo3蛋白的结合亲和力较低，circ-Foxo3阻止MDM2诱导Foxo3泛素化和降解，导致Foxo3蛋白水平升高。因此，Foxo3下游靶点PUMA上调可诱导细胞凋亡。
Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA.