CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
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DOI：
10.1016/j.jbc.2021.100707
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hailong Wang
中科院分区：
文献类型：
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作者：
Jianping Ren;Yan Wu;Ya Wang;Yuqin Zhao;Youhang Li;Shuailin Hao;Lixiu Lin;Shuyuan Zhang;Xingzhi Xu;Hailong Wang
miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs iscontrolled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal–binding protein– interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination–mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer.
