DAB2IP stabilizes p27Kip1 via suppressing PI3K/AKT signaling in clear cell renal cell carcinoma

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Jiancheng Zhou1, Zhuo Deng2, Xinqi Pei1

  • 1Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.

Functional & Integrative Genomics
|October 25, 2023
PubMed

Insights

Loss of DAB2IP protein in renal cell carcinoma (RCC) promotes tumor growth by increasing cell proliferation and decreasing p27 levels. Restoring DAB2IP stabilizes p27, improving survival in clear cell RCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Urology

Background:

  • Renal cell carcinoma (RCC) is a lethal urologic malignancy.
  • DAB2IP (Ras GTPase-activating protein) is frequently epigenetically silenced in RCC.
  • DAB2IP loss correlates with reduced patient survival.

Purpose of the Study:

  • To determine the biological functions of DAB2IP in clear cell RCC (ccRCC).
  • To elucidate the mechanisms by which DAB2IP loss affects ccRCC progression.
  • To analyze the correlation between DAB2IP expression, tumor size, and patient survival.

Main Methods:

  • Correlation analysis of DAB2IP expression with ccRCC tumor size and patient survival.
  • Assessment of cell proliferation, cell cycle progression, and p27 expression following DAB2IP knockdown.
  • Investigation of p27 protein stability, phosphorylation, and degradation pathways.
  • Functional analysis of the DAB2IP C-terminal proline-rich domain (CPR) on AKT and p27 phosphorylation.

Main Results:

  • High DAB2IP mRNA levels correlate with smaller ccRCC tumor size and better patient survival.
  • DAB2IP knockdown increases ccRCC cell proliferation and G1/S phase progression, while decreasing p27 expression.
  • Loss of DAB2IP promotes p27 phosphorylation, cytosolic sequestration, and ubiquitination-mediated degradation.
  • The DAB2IP CPR domain suppresses AKT and p27 phosphorylation.

Conclusions:

  • DAB2IP is crucial for stabilizing p27 protein in ccRCC.
  • DAB2IP loss promotes ccRCC progression, partly via the PI3K/AKT signaling pathway.
  • DAB2IP functions as a tumor suppressor in clear cell renal cell carcinoma.
Keywords:
Clear cell renal cell carcinomaDAB2IPPI3K/AKT pathwayp27

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