Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1
Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1
复制标题
顺式作用 circ-CTNNB1 通过 DDX3 介导的 YY1 反式激活促进 β-连环蛋白信号转导和癌症进展
DOI：
10.1158/0008-5472.can-18-1559
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发表时间：
2019-02-01
期刊：
影响因子：
11.2
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
--
作者：
Yang, Feng;Fang, Erhu;Tong, Qiangsong
环状RNA（CircRNA）是一类以共价闭合的连续环为特征的非编码RNA，在肿瘤的发生和侵袭中发挥着重要作用。然而，circRNA在调节Wnt/β-catenin信号传导和癌症进展中的功能和潜在机制仍然难以捉摸。在这里，我们筛选由β-连环蛋白（CTNNB 1）/转录因子7-like 2基因产生的顺式作用circRNA，并鉴定出一种源自CTNNB 1的内含子circRNA（circ-CTNNB 1）作为癌症进展的新驱动因素。Circ-CTNNB 1主要在细胞核中表达，在癌症组织和细胞系中上调，并与癌症患者的不良结局相关。Circ-CTNNB 1促进癌细胞中的β-连环蛋白活化、生长、侵袭和转移。Circ-CTNNB 1结合DEAD-box多肽3（DDX 3）以促进其与转录因子Yin Yang 1（YY 1）的物理相互作用，导致YY 1的反式激活和与β-连环蛋白激活和癌症进展相关的下游基因的转录改变。在临床前，给予靶向circ-CTNNB 1的慢病毒介导的短发夹RNA或阻断circ-CTNNB 1-DDX 3相互作用的细胞穿透抑制肽抑制了癌细胞中的下游基因表达、肿瘤发生和侵袭性。这些结果表明，circ-CTNNB 1是通过DDX 3介导的YY 1反式激活β-catenin信号通路和肿瘤进展的介导者。意义：这些发现揭示了circ-CTNNB 1在β-catenin激活和肿瘤进展中的致癌功能，具有作为人类肿瘤治疗靶点的潜在价值。
Circular RNAs (circRNA), a subclass of noncoding RNA characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. However, the functions and underlying mechanisms of circRNA in regulating Wnt/beta-catenin signaling and cancer progression remain elusive. Here, we screen cis-acting circRNA generated by beta-catenin (CTNNB1)/transcription factor 7-like 2 genes and identify one intronic circRNA derived from CTNNB1 (circ-CTNNB1) as a novel driver of cancer progression. Circ-CTNNB1 was predominantly expressed in the nucleus, upregulated in cancer tissues and cell lines, and associated with unfavorable outcomes in patients with cancer. Circ-CTNNB1 promoted beta-catenin activation, growth, invasion, and metastasis in cancer cells. Circ-CTNNB1 bound DEAD-box polypeptide 3 (DDX3) to facilitate its physical interaction with transcription factor Yin Yang 1 (YY1), resulting in the transactivation of YY1 and transcriptional alteration of downstream genes associated with beta-catenin activation and cancer progression. Preclinically, administration of lentivirus-mediated short hairpin RNA targeting circ-CTNNB1 or a cell-penetrating inhibitory peptide blocking the circ-CTNNB1-DDX3 interaction inhibited downstream gene expression, tumorigenesis, and aggressiveness in cancer cells. Taken together, these results demonstrate cis-acting circ-CTNNB1 as a mediator of beta-catenin signaling and cancer progression through DDX3-mediated transactivation of YY1.Significance: These findings reveal the oncogenic functions of a cis-acting circular RNA in beta-catenin activation and cancer progression, with potential value as a therapeutic target for human cancers.