SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells
SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells
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SUMOylation 调节 LIN28A-let-7 信号通路以响应癌细胞中的细胞应激
DOI：
10.1002/1878-0261.12694
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发表时间：
2020-06-01
影响因子：
6.6
通讯作者：
Yu, Jianxiu
中科院分区：
文献类型：
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作者：
Dou, Jinzhuo;Zhang, Hailong;Yu, Jianxiu
LIN 28 A是一种保守的RNA结合蛋白，可抑制let-7 microRNA的生物合成，从而促进癌症进展。然而，LIN 28 A-let-7信号通路激活的潜在机制仍然知之甚少。在这里，我们表明LIN 28 A在体内和体外在K15处被SUMO化，其通过缺氧而增加，但通过化疗药物如顺铂和紫杉醇而减少。LIN 28 A的SUMO化增强了其对let-7成熟的抑制，导致let-7的明显减少，这促进了癌细胞的增殖、迁移、侵袭和体内肿瘤生长。从机制上讲，LIN 28 A的SUMO化增加了其与前体let-7（pre-let-7）的结合亲和力，这随后增强了LIN 28 A介导的末端尿苷酰转移酶TUT 4的募集，同时阻断了pre-let-7的DICER加工，从而减少了成熟let-7的产生。这些作用在SUMO化缺陷突变体LIN 28 A-K15 R中被消除。总之，这些发现揭示了SUMO化可以调节LIN 28 A-let-7途径以响应癌细胞细胞应激的新机制。
LIN28A is a conserved RNA-binding protein that inhibits the biogenesis of let-7 microRNAs, thus promoting cancer progression. However, mechanisms underlying the activation of the LIN28A-let-7 signaling pathway remain poorly understood. Here, we show that LIN28A is SUMOylated in vivo and in vitro at K15, which is increased by hypoxia but reduced by chemotherapy drugs such as Cisplatin and Paclitaxel. SUMOylation of LIN28A aggravates its inhibition of let-7 maturation, resulting in a stark reduction in let-7, which promotes cancer cell proliferation, migration, invasion, and tumor growth in vivo. Mechanistically, SUMOylation of LIN28A increases its binding affinity with the precursor let-7 (pre-let-7), which subsequently enhances LIN28A-mediated recruitment of terminal uridylyltransferase TUT4 and simultaneously blocks DICER processing of pre-let-7, thereby reducing mature let-7 production. These effects are abolished in SUMOylation-deficient mutant LIN28A-K15R. In summary, these findings shed light on a novel mechanism by which SUMOylation could regulate the LIN28A-let-7 pathway in response to cellular stress in cancer cells.