Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes.
CP: Molecular biology
KRAS
KZNF
RAS signaling
RNA biomarker
cancer
extracellular RNA
extracellular vesicles
interferon-stimulated genes
noncoding RNA
transposable element
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
19 07 2022
19 07 2022
Historique:
received:
08
11
2020
revised:
04
04
2022
accepted:
27
06
2022
entrez:
20
7
2022
pubmed:
21
7
2022
medline:
23
7
2022
Statut:
ppublish
Résumé
RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.
Identifiants
pubmed: 35858545
pii: S2211-1247(22)00906-8
doi: 10.1016/j.celrep.2022.111104
pmc: PMC9374308
mid: NIHMS1824946
pii:
doi:
Substances chimiques
DNA Transposable Elements
0
KRAS protein, human
0
RNA
63231-63-0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
111104Subventions
Organisme : NIDDK NIH HHS
ID : F99 DK131504
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227807
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230263
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239604
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.H.K. and R.E.R. are inventors on patent applications covering the methods and compositions to detect cancer using extracellular RNA submitted by the Regents of the University of California. D.H.K. and spouse are founders and shareholders in and D.H.K. is a board member of LincRNA Bio.
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