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Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A

Roberta Cacioppo1, Hesna Begum Akman1,2, Taner Tuncer3

  • 1Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.

Elife
|June 29, 2023
PubMed

Insights

Alternative polyadenylation (APA) and miRNA targeting control Aurora Kinase A (AURKA) oncogenic functions. A short AURKA mRNA isoform promotes cancer progression by increasing proliferation and migration, correlating with faster relapse in triple-negative breast cancer patients.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Aurora Kinase A (AURKA) is an oncogenic kinase critical for mitosis and cancer progression.
  • AURKA also has cell cycle- and kinase-independent functions in cancer.
  • Control of AURKA expression and activity is essential.

Purpose of the Study:

  • To investigate the role of alternative polyadenylation (APA) and miRNA targeting in AURKA regulation.
  • To understand the functional differences between AURKA mRNA 3'UTR isoforms.
  • To elucidate a novel mechanism of oncogenic activation of AURKA.

Main Methods:

  • Analysis of AURKA mRNA 3'UTR isoforms (short and long) using alternative polyadenylation (APA).
  • Investigation of miRNA targeting, specifically hsa-let-7a, on AURKA isoforms.
  • Assessment of translational efficiency, decay rates, and cell cycle periodicity of AURKA isoforms.
  • Evaluation of cell proliferation and migration rates upon disruption of long AURKA isoform production.

Main Results:

  • Triple-negative breast cancer exhibits predominant short AURKA mRNA isoform, correlating with faster patient relapse.
  • The short AURKA isoform has higher translational efficiency compared to the long isoform.
  • hsa-let-7a tumor-suppressor miRNA targets the long AURKA isoform, regulating its translation and decay.
  • The short AURKA isoform is translated constantly, while the long isoform's translation is cell cycle-periodical.
  • Disruption of the long AURKA isoform increases cell proliferation and migration.

Conclusions:

  • A novel mechanism involving the interplay of APA and miRNA targeting contributes to AURKA oncogenic activation.
  • The short AURKA mRNA isoform promotes cancer progression through enhanced translation and constant expression.
  • This mechanism represents a potential route for oncogenic activation of AURKA in human cancers.
Keywords:
3′ UTRAURKAcell biologycell cyclechromosomesgene expressionhumanmiRNAtranslation

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