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Epigenetic and proteolytic inactivation of 14-3-3sigma in breast and prostate cancers

Kuniko Horie-Inoue1, Satoshi Inoue

  • 1Research Center for Genomic Medicine and Department of Molecular Biology, Saitama Medical School, Hidaka-shi, Japan.

Seminars in Cancer Biology
|May 10, 2006
PubMed

Insights

Loss of 14-3-3sigma, a protein involved in cell cycle arrest, is common in breast and prostate cancers due to genetic and epigenetic changes. This inactivation presents a potential target for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • 14-3-3sigma is an epithelial marker induced by DNA damage via a p53-dependent pathway.
  • It functions in G2 cell cycle arrest by sequestering cyclin B1-CDC2 complexes.
  • Loss of 14-3-3sigma is frequent in breast and prostate cancers.

Purpose of the Study:

  • To investigate the mechanisms of 14-3-3sigma down-regulation in cancer.
  • To explore the potential of 14-3-3sigma as a prognostic marker and therapeutic target.

Main Methods:

  • Analysis of epigenetic silencing (CpG methylation).
  • Investigation of p53 inactivation and proteasome-dependent proteolysis.
  • Identification of E3 ubiquitin ligase Efp and UBC8 in 14-3-3sigma degradation and ISG15 modification.

Main Results:

  • Epigenetic silencing via CpG methylation and p53 inactivation lead to loss of 14-3-3sigma.
  • Hypermethylation is observed in precancerous lesions, suggesting a role in cancer onset.
  • Proteolytic inactivation, mediated by Efp and UBC8, is found in breast and prostate cancers.
  • Efp targets 14-3-3sigma for degradation and UBC8 mediates ISG15 modification.

Conclusions:

  • 14-3-3sigma inactivation occurs through multiple mechanisms including epigenetic silencing and proteolysis.
  • Detection of 14-3-3sigma inactivation may serve as a prognostic tool for cancer.
  • 14-3-3sigma represents a potential therapeutic target for breast and prostate cancers.

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