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Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2

Zhiwei Wang1, Hiroyuki Inuzuka, Jiateng Zhong

  • 1Department of Pathology, Harvard Medical School, Boston, MA, USA.

Oncotarget
|December 12, 2012
PubMed

Insights

The S-phase kinase associated protein 2 (Skp2) oncoprotein

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • S-phase kinase associated protein 2 (Skp2) is an oncoprotein frequently overexpressed in human cancers.
  • The precise mechanisms driving Skp2's oncogenic activity and its regulatory pathways are not fully understood.
  • Understanding Skp2 regulation is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the acetylation-dependent regulatory mechanism of Skp2.
  • To identify the upstream regulators and downstream targets of Skp2.
  • To investigate the role of Skp2 acetylation in cancer progression.

Main Methods:

  • Investigated the acetylation of Skp2 by p300 at lysine residues K68 and K71 within its nuclear localization signal (NLS).
  • Assessed the impact of acetylation on Skp2 stability and subcellular localization.
  • Identified SIRT3 as the deacetylase counteracting p300-mediated Skp2 acetylation.
  • Examined Skp2's role in E-cadherin ubiquitination and degradation.
  • Analyzed the correlation between Skp2 and E-cadherin expression in clinical breast tumor samples.

Main Results:

  • p300 acetylates Skp2 at K68 and K71, enhancing its stability and promoting cytoplasmic translocation, thereby increasing its oncogenic potential.
  • SIRT3 functions as the physiological deacetylase, opposing p300-mediated Skp2 acetylation.
  • Skp2 mediates the ubiquitination and degradation of E-cadherin in the cytosol.
  • An inverse correlation between Skp2 and E-cadherin expression was observed in clinical breast tumors.

Conclusions:

  • A novel acetylation-dependent regulatory mechanism controlling Skp2 oncogenic functions has been elucidated.
  • The interplay between p300, SIRT3, and Skp2 acetylation regulates Skp2 stability and localization.
  • Skp2-mediated E-cadherin degradation contributes to its oncogenic role, with potential clinical implications in breast cancer.

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