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Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key

Edward Hitti1, Tala Bakheet1, Norah Al-Souhibani1

  • 1Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Cancer Research
|May 20, 2016
PubMed

Insights

Defects in AU-rich elements (AREs) impact cancer by altering RNA regulation. This study identifies a specific ARE-mRNA cluster linked to cell division that is overexpressed in many cancers, correlating with poor patient survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Posttranscriptional Regulation

Background:

  • AU-rich elements (AREs) are crucial for posttranscriptional control of gene expression.
  • Dysregulation of ARE-mediated pathways is implicated in various cancers.
  • The balance of RNA-binding proteins like tristetraprolin (TTP) and HuR is critical in cancer development.

Purpose of the Study:

  • To systematically analyze ARE-mRNA expression across diverse cancer types.
  • To identify specific ARE-mRNAs and RNA-binding protein (RBP) signatures associated with cancer.
  • To investigate the functional role of AREs and RBPs in cancer, particularly in relation to the cell cycle.

Main Methods:

  • Intersection of the ARE database (ARED) with The Cancer Genome Atlas (TCGA) and other cancer datasets.
  • Statistical and functional enrichment analysis to identify key ARE-mRNA clusters.
  • Experimental validation in cancer cell lines, including RNA immunoprecipitation (RIP) and reporter assays.
  • Flow cytometry and Western blotting to assess cell cycle effects and protein phosphorylation.

Main Results:

  • A significant number of ARE-mRNAs were over-represented in cancer, correlating with altered TTP/HuR expression ratios.
  • A specific cluster of 11 ARE-mRNAs involved in the mitotic cell cycle was identified as upregulated in multiple solid cancers.
  • This mitotic ARE-mRNA signature was elevated in tumor breast cell lines and negatively correlated with TTP/HuR mRNA ratios.
  • TTP demonstrated an antimitotic effect, and its experimental modulation impacted mitotic ARE-mRNAs.
  • Low TTP/HuR mRNA ratios and high levels of the mitotic ARE-mRNA signature were associated with poor breast cancer patient survival.

Conclusions:

  • AREs and their associated RNA-binding proteins play a significant role in cancer pathogenesis.
  • A specific set of ARE-mRNAs involved in mitosis is dysregulated in cancer.
  • TTP induces an antimitotic pathway that is compromised in cancer, contributing to tumor progression and poor prognosis.

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