Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation

Cancer Cell. 2019 Jan 14;35(1):81-94.e7. doi: 10.1016/j.ccell.2018.11.017. Epub 2019 Jan 3.

Abstract

Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.

Keywords: 3′ UTR; ADAR1; RNA hyper-editing; cancer stem cell; cell cycle; chronic myeloid leukemia; epitranscriptome; leukemia; microRNAs; progenitors; self-renewal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adenosine Deaminase / genetics*
  • Animals
  • Blast Crisis / genetics*
  • Cell Cycle
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Female
  • Gene Editing
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • HEK293 Cells
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • RNA-Binding Proteins / genetics*

Substances

  • 3' Untranslated Regions
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN26A microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • ADAR1 protein, human
  • Adenosine Deaminase