Open AccessSUMOylation modulates the LIN28A‐let‐7 signaling pathway in response to cellular stresses in cancer cells
Author(s) -
Dou Jinzhuo,
Zhang Hailong,
Chen Ran,
Shu Zimei,
Yuan Haihua,
Zhao Xian,
Wang Yanli,
Huang Jian,
Zhou Aiwu,
Yu Jianxiu
Publication year - 2020
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12694
Subject(s) - sumo protein , microbiology and biotechnology , cancer cell , chemistry , microrna , paclitaxel , dicer , cisplatin , gene silencing , in vivo , cancer research , biology , cancer , rna , biochemistry , genetics , rna interference , chemotherapy , ubiquitin , gene
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.