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Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1

Y Deng1, J Liu, G Han

  • 1Department of Dermatology, University of Colorado, Denver, Aurora, CO 80045, USA.

Oncogene
|September 7, 2010
PubMed

Insights

C-terminal binding protein 1 (CtBP1) represses the tumor suppressor Brca1 in head and neck cancers. Blocking CtBP1 activity with antioxidants may offer a new therapeutic strategy for head and neck squamous cell carcinomas (HNSCCs).

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Metabolic Regulation

Background:

  • C-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that often represses tumor suppressor genes.
  • Brca1 downregulation is an early event in head and neck squamous cell carcinomas (HNSCCs).

Purpose of the Study:

  • To investigate if CtBP1 affects Brca1 expression in head and neck tissue.
  • To elucidate the mechanism of CtBP1-mediated Brca1 repression and its potential as a therapeutic target.

Main Methods:

  • Analysis of CtBP1 binding to the Brca1 promoter using molecular techniques.
  • Assessment of CtBP1 recruitment dependency on NADH levels and hypoxia.
  • Immunostaining of human HNSCC tissue arrays.
  • Pharmacological inhibition of CtBP1 activity using Tempol.

Main Results:

  • CtBP1 represses Brca1 transcription by binding to the E2F4 site on the Brca1 promoter.
  • CtBP1 recruitment to the Brca1 promoter is redox-dependent, increasing with high NADH levels under hypoxia.
  • Nuclear CtBP1 accumulation correlates with Brca1 downregulation in HNSCC lesions.
  • Tempol treatment relieved CtBP1-mediated repression, increasing Brca1 expression and DNA repair in HNSCC cells.

Conclusions:

  • CtBP1 acts as a metabolic switch, linking tumor metabolism to tumor suppressor expression in HNSCC.
  • Blocking NADH-dependent CtBP1 activity presents a potential chemo-preventative or therapeutic strategy for HNSCC.
  • Findings provide insights into the early stages of HNSCC carcinogenesis and suggest novel therapeutic avenues.

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