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Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients

Ruo-Chia Tseng1, Chin-Chu Lee, Han-Shui Hsu

  • 1Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan, ROC.

Neoplasia (New York, N.Y.)
|August 4, 2009
PubMed

Insights

The HIC1-SIRT1-p53 loop is deregulated in lung cancer, impacting prognosis. Alterations in this pathway, including p53 acetylation and HIC1 expression, are linked to poor patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • The hypermethylation in cancer 1 (HIC1)-SIRT1-p53 pathway is a known regulatory loop in cancer models.
  • Its clinical relevance and prognostic impact in human lung cancer patients remained uncharacterized.

Purpose of the Study:

  • To investigate the alterations and prognostic significance of the HIC1-SIRT1-p53 circular loop in human lung cancer.
  • To elucidate the distinct mechanisms of HIC1-SIRT1-p53 deregulation in lung squamous cell carcinoma and lung adenocarcinoma.

Main Methods:

  • Analysis of HIC1, SIRT1, p53 acetylation, and deleted in breast cancer 1 (DBC1) expression in 118 lung cancer patients.
  • Examination of epigenetic modifications, including promoter hypermethylation and histone modifications, of the HIC1 gene.
  • Correlation of molecular findings with patient prognosis.

Main Results:

  • Deregulation of the HIC1-SIRT1-p53 loop was confirmed in lung cancer patients, with low HIC1 expression correlating with low p53 acetylation and SIRT1 expression in squamous cell carcinoma.
  • DBC1 expression influenced p53 acetylation in lung adenocarcinoma, while epigenetic alterations of the HIC1 promoter attenuated its transcriptional induction.
  • Altered HIC1-SIRT1-p53 circular regulation was significantly associated with poor prognosis in lung cancer patients.

Conclusions:

  • This study provides the first clinical evidence for the deregulation of the HIC1-SIRT1-p53 loop in lung tumorigenesis and its prognostic implications.
  • Distinct mechanisms involving SIRT1-DBC1 interaction and epigenetic alterations drive the differential regulation of this pathway in lung squamous cell carcinoma and lung adenocarcinoma.

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