An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2

EMBO J. 2020 Dec 15;39(24):e104719. doi: 10.15252/embj.2020104719. Epub 2020 Nov 20.

Abstract

Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which causes haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and a mouse model of AGCT, abundance of the inversely regulated variant FOXL2 with miR-1236 levels is highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.

Keywords: Argonaute3; DHX9; allelic imbalance; metastasis; miR-1236.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allelic Imbalance
  • Animals
  • Apoptosis
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism
  • Cell Death / physiology
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Forkhead Box Protein L2 / genetics*
  • Forkhead Box Protein L2 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Granulosa Cell Tumor / genetics*
  • Granulosa Cell Tumor / pathology
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mutation*
  • Mutation, Missense
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Open Reading Frames*
  • RNA, Messenger / metabolism
  • Transcriptome

Substances

  • AGO3 protein, human
  • Argonaute Proteins
  • FOXL2 protein, human
  • Forkhead Box Protein L2
  • Foxl2 protein, mouse
  • MIRN1236 microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Messenger
  • DHX9 protein, human
  • DEAD-box RNA Helicases