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Updated: Jul 24, 2025

Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library
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Oncogenic K-Ras suppresses global miRNA function

Bing Shui1, Tyler S Beyett2, Zhengyi Chen3

  • 1Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Program in Biological and Biomedical Sciences, Division of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|July 4, 2023
PubMed

Insights

Oncogenic K-Ras (G12D) suppresses microRNA (miRNA) activity, leading to increased miRNA targets. This occurs via reduced Ago2 phosphorylation, impacting gene expression in cancer development.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • K-Ras mutations drive tumorigenesis through transcriptomic and proteomic alterations.
  • The role of microRNAs (miRNAs) in oncogenic K-Ras-driven cancer is not well understood.

Purpose of the Study:

  • To investigate how K-Ras mutations impact miRNA activity and target regulation during oncogenesis.
  • To elucidate the molecular mechanisms linking K-Ras to post-transcriptional gene dysregulation.

Main Methods:

  • Halo-enhanced Argonaute pull-down to profile miRNA targets in mouse colonic epithelium and K-RasG12D tumors.
  • Integration of datasets for chromatin accessibility, transcriptome, and proteome.
  • Analysis of Ago2 phosphorylation and its impact on mRNA binding and repression activity.

Main Results:

  • K-RasG12D globally suppresses miRNA activity, leading to hundreds of upregulated miRNA targets.
  • K-RasG12D reduces expression of Csnk1a1 and Csnk2a1, decreasing Ago2 phosphorylation.
  • Hypo-phosphorylated Ago2 binds mRNAs more but represses miRNA targets less effectively.

Conclusions:

  • K-RasG12D dysregulates global miRNA activity through Ago2 hypo-phosphorylation.
  • This provides a mechanistic link between oncogenic K-Ras and post-transcriptional upregulation of miRNA targets.
  • Identifies a novel regulatory pathway in K-Ras-driven tumorigenesis.
Keywords:
Ago2CLIP-seqK-Rascasein kinasecoloncolorectal cancermiRNA

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