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Modification of p27 with O-linked N-acetylglucosamine regulates cell proliferation in hepatocellular carcinoma

Huiyuan Qiu1,2, Fang Liu3, Tao Tao2

  • 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, PR China.

Molecular Carcinogenesis
|May 14, 2016
PubMed

Insights

O-GlcNAcylation of the tumor suppressor p27 at Ser2 promotes hepatocellular carcinoma cell proliferation by altering its phosphorylation and localization. This dynamic interplay regulates cell cycle progression and tumor growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • p27 is a tumor suppressor protein controlling cell proliferation.
  • Post-translational O-GlcNAcylation is a key regulatory modification.
  • Dysregulation of p27 is implicated in hepatocellular carcinoma (HCC).

Purpose of the Study:

  • To investigate the role of O-GlcNAcylation on p27.
  • To determine the functional consequences of p27 O-GlcNAcylation in HCC.
  • To elucidate the interplay between p27 O-GlcNAcylation and phosphorylation.

Main Methods:

  • O-GlcNAcylation site identification using Q-TOF mass spectrometry.
  • Immunoprecipitation and western blot analysis.
  • Analysis of HCC tissues and cell lines (HEK293T, HCC).

Main Results:

  • Identified Ser2, Ser106, Ser110, Thr157, and Thr198 as O-GlcNAcylation sites on p27.
  • O-GlcNAcylation at Ser2 increased p27 phosphorylation at Ser10, leading to cytoplasmic accumulation and ubiquitination.
  • O-GlcNAcylation at Ser2 promoted nuclear export, suppressed Cyclin/CDK interactions, and facilitated cell cycle progression.
  • Mutating Ser2 to Ala negatively regulated cell proliferation.
  • O-GlcNAcylated p27 correlated with cell proliferation in HCC tissues.

Conclusions:

  • O-GlcNAcylation at Ser2 of p27 plays a critical role in regulating cell proliferation in HCC.
  • The dynamic interplay between O-GlcNAcylation and phosphorylation of p27 coordinates cell cycle progression.
  • Targeting p27 O-GlcNAcylation may offer a therapeutic strategy for hepatocellular carcinoma.
Keywords:
HCCO-GlcNAcylationp27kip1phosphorylationtumor promotion

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