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O-GlcNAcylation-mediated degradation of FBXL2 stabilizes FOXM1 to induce cancer progression

Yasuhiro Ueda1, Kazumasa Moriwaki2, Toshihisa Takeuchi1

  • 1Second Department of Internal Medicine, Faculty of Medicine, Osaka Medical College, Osaka, 569-8686, Japan.

Biochemical and Biophysical Research Communications
|November 5, 2019
PubMed

Insights

Elevated O-GlcNAcylation, a hallmark of cancer, promotes tumor growth by inhibiting the degradation of the oncogenic FOXM1 protein via FBXL2 E3 ubiquitin ligase. This finding reveals a new mechanism in cancer progression.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • O-GlcNAcylation is a crucial post-translational modification regulating cellular signaling and is elevated in cancer.
  • FOXM1, an oncogenic transcription factor, is overexpressed in solid tumors and its expression is increased by O-GlcNAcase inhibitors like Thiamet G (TMG).

Purpose of the Study:

  • To investigate the role of O-GlcNAcylation in regulating FOXM1 stability and cancer progression.
  • To identify new targets of O-GlcNAcylation involved in FOXM1 regulation.

Main Methods:

  • Utilized gastric cancer cell lines (MKN45, NUGC-3).
  • Administered O-GlcNAcase inhibitor Thiamet G (TMG).
  • Assessed protein expression, ubiquitination, and degradation using Western blotting and immunoprecipitation.

Main Results:

  • Identified FBXL2 E3 ubiquitin ligase as a novel O-GlcNAcylation target.
  • TMG treatment increased O-GlcNAcylation, decreased FOXM1 ubiquitination and degradation, and increased FOXM1 expression.
  • FBXL2 directly ubiquitinated FOXM1, and TMG reduced this interaction and FOXM1 ubiquitination.
  • TMG promoted FBXL2 ubiquitination, suggesting O-GlcNAcylation stabilizes FBXL2.
  • Reduced FBXL2 expression decreased FOXM1 levels and cell proliferation, effects attenuated by TMG.

Conclusions:

  • Elevated O-GlcNAcylation stabilizes FOXM1 by inhibiting FBXL2-mediated degradation, thereby promoting gastric cancer progression.
  • FBXL2 is a key regulator of FOXM1 stability, and its degradation is modulated by O-GlcNAcylation.
  • Targeting O-GlcNAcylation may offer a therapeutic strategy for cancers driven by FOXM1.
Keywords:
Cancer progressionFBXL2FOXM1O-GlcNAcylationUbiquitination

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