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

Qingfei Jiang; Jane Isquith; Maria Anna Zipeto; Raymond H Diep; Jessica Pham; Nathan Delos Santos; Eduardo Reynoso; Julisia Chau; Heather Leu; Elisa Lazzari; Etienne Melese; Wenxue Ma; Rongxin Fang; Mark Minden; Sheldon Morris; Bing Ren; Gabriel Pineda; Frida Holm; Catriona Jamieson

doi:10.1016/j.ccell.2018.11.017

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.

Authors

Qingfei Jiang¹, Jane Isquith², Maria Anna Zipeto², Raymond H Diep², Jessica Pham², Nathan Delos Santos², Eduardo Reynoso², Julisia Chau², Heather Leu², Elisa Lazzari², Etienne Melese³, Wenxue Ma², Rongxin Fang⁴, Mark Minden⁵, Sheldon Morris⁶, Bing Ren⁷, Gabriel Pineda⁸, Frida Holm², Catriona Jamieson⁹

Affiliations

¹ Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: [email protected].
² Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
³ Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁴ Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Princess Margaret Hospital, Toronto, ON M5T 2M9, Canada.
⁶ Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA.
⁷ Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
⁸ Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Health Sciences, School of Health and Human Services, National University, San Diego, CA, USA.
⁹ Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: [email protected].

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
ADAR protein, human
Adenosine Deaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding