SUMOylation modulates the LIN28A‐let‐7 signaling pathway in response to cellular stresses in cancer cells

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. This study demonstrated that SUMOylation of LIN28A increases the binding affinity of LIN28A with pre‐let‐7, subsequently to promote TUT4‐mediated uridylation and block DICER processing of pre‐let‐7, thus leading to the reduction of mature let‐7. SUMOylation of Lin28A is regulated in response to cancer cellular stresses such as hypoxia and chemotherapy drug treatment, which have implications in cancer prognosis and therapy.