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Functional interaction of DNA topoisomerase IIalpha with the beta-catenin and T-cell factor-4 complex

Lin Huang1, Miki Shitashige, Reiko Satow

  • 1Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo, Japan.

Gastroenterology
|November 7, 2007
PubMed
Abstract

Insights

DNA topoisomerase IIalpha (Topo IIalpha) acts as a co-activator in colorectal cancer by interacting with beta-catenin. Targeting this interaction may offer a more effective therapy for colorectal cancer than current Topo II inhibitors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • The Wnt signaling pathway is frequently activated in colorectal cancer due to mutations in adenomatous polyposis coli or CTNNB1.
  • DNA topoisomerase IIalpha (Topo IIalpha) is a component of the beta-catenin/T-cell factor-4 (TCF-4) nuclear complex, suggesting a role in Wnt signaling.

Purpose of the Study:

  • To investigate the functional significance of Topo IIalpha in Wnt signaling within the context of colorectal cancer.
  • To determine the interaction between Topo IIalpha and the beta-catenin/TCF-4 complex.

Main Methods:

  • Evaluated the physical and functional interaction using immunoprecipitation, immunofluorescence microscopy, 2-hybrid assay, and luciferase reporter assay.
  • Assessed Topo IIalpha's catalytic activity via kinetoplast DNA decatenation.
  • Examined Topo IIalpha expression in patient tumor samples.

Main Results:

  • Topo IIalpha binds to beta-catenin via amino acids 951-1301.
  • Overexpression of Topo IIalpha enhanced TCF/lymphoid enhancer factor transcriptional activity, while knockdown attenuated it.
  • Topo II inhibitors suppressed beta-catenin-mediated transcriptional activity, and Topo II catalytic activity was augmented by beta-catenin overexpression.
  • High expression and co-localization of Topo IIalpha and beta-catenin were observed in colorectal tumors.

Conclusions:

  • Topo IIalpha functions as a novel transcriptional co-activator by interacting with beta-catenin.
  • Targeting the Topo IIalpha-beta-catenin interaction and Topo IIalpha's catalytic activity could be a superior therapeutic strategy for colorectal cancer.

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