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Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes

Roman E Reggiardo1, Sreelakshmi Velandi Maroli2, Haley Halasz2

  • 1Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.

Cell Reports
|July 20, 2022
PubMed

Insights

Oncogenic RAS signaling, common in cancer, alters noncoding RNAs, particularly those from transposable elements (TEs). Mutant KRAS remodels the transcriptome, impacting cellular and extracellular RNA, with implications for cancer progression.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Transcriptomics

Background:

  • RAS genes are frequently mutated oncogenes in various cancers.
  • The impact of oncogenic RAS signaling on the noncoding transcriptome is not well understood.

Purpose of the Study:

  • To investigate the effects of oncogenic RAS signaling on noncoding RNA.
  • To define the landscape of KRAS-regulated noncoding RNAs in human airway and bronchial epithelial cells.

Main Methods:

  • Analysis of transcriptomes from human airway and bronchial epithelial cells engineered with mutant KRAS.
  • Investigated differential expression of transposable element (TE) RNAs.
  • Examined regulation by KRAB zinc-finger (KZNF) genes and induction of IFN-stimulated gene (ISG) signatures.

Main Results:

  • Oncogenic KRAS signaling upregulates noncoding transcripts, including many from TEs.
  • TE RNAs show differential expression, are released in extracellular vesicles, and are regulated by downregulated KZNF genes.
  • Mutant KRAS induces an IFN-stimulated gene (ISG) signature observed in many cancers.

Conclusions:

  • Mutant KRAS significantly remodels the repetitive noncoding transcriptome.
  • This pathway broadly regulates both intracellular and extracellular RNAs.
  • Findings highlight the extensive impact of oncogenic RAS signaling on RNA regulation in cancer.
Keywords:
CP: Molecular biologyKRASKZNFRAS signalingRNA biomarkercancerextracellular RNAextracellular vesiclesinterferon-stimulated genesnoncoding RNAtransposable element

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