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Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent

Tijana Šopin1, František Liška1, Tomáš Kučera2

  • 1Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech Republic.

Cells
|November 24, 2023
PubMed

Insights

The lysine demethylase KDM2A targets TCF/LEF transcription factors for proteasomal degradation, independent of its demethylase activity. This discovery reveals a new regulatory mechanism for canonical Wnt signaling.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Canonical Wnt signaling is vital for development and implicated in diseases like cancer.
  • TCF/LEF transcription factors are key mediators of Wnt signaling, but their regulation is not fully understood.

Purpose of the Study:

  • To investigate the role of lysine demethylase KDM2A in regulating TCF/LEF transcription factors.
  • To elucidate the mechanism by which KDM2A affects TCF/LEF protein levels.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to assess protein levels and degradation.
  • Ubiquitination and neddylation assays to investigate post-translational modifications.

Main Results:

  • KDM2A promotes the proteasomal degradation of TCF/LEFs via its CXXC domain, not its demethylase domain.
  • The C-terminal region of TCF7L2 interacts with KDM2A's CXXC domain.
  • Endogenous TCF/LEF degradation is neddylation-dependent and mediated by KDM2A.

Conclusions:

  • KDM2A acts as a novel regulator of Wnt signaling by targeting TCF/LEFs for proteasomal degradation.
  • This mechanism involves KDM2A's CXXC domain and neddylation.
  • Understanding this pathway offers new insights into Wnt signaling dysregulation in diseases.
Keywords:
KDM2ATCF/LEFcanonical Wnt signalingneddylationubiquitination

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