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3' UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk

Hyun Jung Park1,2,3, Ping Ji4, Soyeon Kim5

  • 1Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.

Nature Genetics
|May 23, 2018
PubMed

Insights

mRNA 3' untranslated region (UTR) shortening surprisingly represses tumor-suppressor genes. This process disrupts competing endogenous RNA (ceRNA) crosstalk, impacting cancer growth rather than promoting proto-oncogenes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Widespread mRNA 3' untranslated region (UTR) shortening, driven by alternative polyadenylation, is linked to tumor growth.
  • A common hypothesis suggests this shortening enhances proto-oncogene expression by evading microRNA repression.
  • However, the precise mechanisms and broader implications remain under investigation.

Purpose of the Study:

  • To investigate the role of 3' UTR shortening in regulating gene expression, particularly concerning tumor-suppressor genes.
  • To explore the impact of 3' UTR shortening on competing endogenous RNA (ceRNA) networks.
  • To elucidate the trans effects of 3' UTR shortening on gene regulation in cancer.

Main Methods:

  • Developed a model-based analysis (MAT3UTR) to assess the trans effects of 3' UTR shortening.
  • Analyzed the enrichment of 3' UTR shortening in transcripts acting as ceRNAs for tumor-suppressor genes.
  • Utilized knockdown experiments of key regulators like NUDT21 to observe effects on tumor-suppressor gene expression.

Main Results:

  • Identified significant enrichment of 3' UTR shortening in ceRNA transcripts targeting tumor-suppressor genes.
  • MAT3UTR analysis revealed 3' UTR shortening alters ceRNA expression, predicting trans-targets like PTEN.
  • Knockdown of NUDT21 led to repression of tumor-suppressor genes (PHF6, LARP1) in trans via miRNA-dependent mechanisms.

Conclusions:

  • 3' UTR shortening plays a significant role in repressing tumor-suppressor genes in trans.
  • This repression occurs through the disruption of ceRNA crosstalk, contrary to the hypothesis of cis-acting proto-oncogene induction.
  • Findings suggest a novel mechanism by which 3' UTR shortening contributes to cancer progression.

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