SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells
Open Access
- 1 September 2020
- journal article
- research article
- Published by Wiley in Molecular Oncology
- Vol. 14 (9), 2288-2312
- https://doi.org/10.1002/1878-0261.12694
Abstract
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.Funding Information
- National Natural Science Foundation of China (81702837, 81902866, 81802563, 81721004, 31671345, 81630075)
This publication has 60 references indexed in Scilit:
- A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28–let-7 pathwayNature, 2013
- SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membraneNature Communications, 2012
- Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct MechanismsCell, 2011
- Molecular Basis for Interaction of let-7 MicroRNAs with Lin28Cell, 2011
- Dicer recognizes the 5′ end of RNA for efficient and accurate processingNature, 2011
- Lin28 promotes transformation and is associated with advanced human malignanciesNature Genetics, 2009
- PTEN regulation by Akt–EGR1–ARF–PTEN axisThe EMBO Journal, 2008
- Lin28 Mediates the Terminal Uridylation of let-7 Precursor MicroRNAMolecular Cell, 2008
- MicroRNA expression profiles classify human cancersNature, 2005
- The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNACell, 1997