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

Y. Deng, J. Liu, G. Han, S. L. Lu, S. Y. Wang, S. Malkoski, Aik-Choon Tan, C. Deng, X. J. Wang, Q. Zhang

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

C-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor and metabolic sensory protein, which often represses tumor suppressor genes. Hence, we sought to determine if CtBP1 affects expression of the tumor suppressor Brca1 in head and neck tissue, as downregulation of Brca1 begins at the early stages of head and neck squamous cell carcinomas (HNSCCs). We found that CtBP1 represses Brca1 transcription by binding to the E2F4 site of the Brca1 promoter. Additionally, the recruitment of CtBP1 to the Brca1 promoter is redox-dependent, that is, increased at high NADH levels in hypoxic conditions. Further, immunostaining using a human HNSCC tissue array revealed that nuclear CtBP1 staining began to accumulate in hyperplasic lesions and HNSCCs, this staining correlated with Brca1 downregulation in these lesions. Pharmacological disruption of CtBP1 binding to Brca1 promoter by the antioxidant Tempol, which reduces NADH levels, relieved CtBP1-mediated repression of Brca1, leading to increased DNA repair in HNSCC cells. As tumor cells are generally hypoxic with increased NADH levels, the dynamic control of Brca1 by a metabolic switch found in this study not only provides an important link between tumor metabolism and tumor suppressor expression but also suggests a potential chemo preventative or therapeutic strategy for HNSCC by blocking NADH-dependent CtBP1 activity at early stages of HNSCC carcinogenesis.

Original languageEnglish
Pages (from-to)6603-6608
Number of pages6
JournalOncogene
Volume29
Issue number50
DOIs
Publication statusPublished - 2010 Dec 16
Externally publishedYes

Fingerprint

NAD
Oxidation-Reduction
Neoplasms
Down-Regulation
Staining and Labeling
Co-Repressor Proteins
C-terminal binding protein
Tumor Suppressor Genes
Protein Binding
DNA Repair
Carcinoma, squamous cell of head and neck
Carcinogenesis
Neck
Antioxidants
Head
Pharmacology
Proteins

Keywords

  • Brca1
  • CtBP1
  • HNSCC
  • NADH
  • transcription
  • tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Deng, Y., Liu, J., Han, G., Lu, S. L., Wang, S. Y., Malkoski, S., ... Zhang, Q. (2010). Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. Oncogene, 29(50), 6603-6608. https://doi.org/10.1038/onc.2010.406

Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. / Deng, Y.; Liu, J.; Han, G.; Lu, S. L.; Wang, S. Y.; Malkoski, S.; Tan, Aik-Choon; Deng, C.; Wang, X. J.; Zhang, Q.

In: Oncogene, Vol. 29, No. 50, 16.12.2010, p. 6603-6608.

Research output: Contribution to journalArticle

Deng, Y, Liu, J, Han, G, Lu, SL, Wang, SY, Malkoski, S, Tan, A-C, Deng, C, Wang, XJ & Zhang, Q 2010, 'Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1', Oncogene, vol. 29, no. 50, pp. 6603-6608. https://doi.org/10.1038/onc.2010.406
Deng Y, Liu J, Han G, Lu SL, Wang SY, Malkoski S et al. Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. Oncogene. 2010 Dec 16;29(50):6603-6608. https://doi.org/10.1038/onc.2010.406
Deng, Y. ; Liu, J. ; Han, G. ; Lu, S. L. ; Wang, S. Y. ; Malkoski, S. ; Tan, Aik-Choon ; Deng, C. ; Wang, X. J. ; Zhang, Q. / Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. In: Oncogene. 2010 ; Vol. 29, No. 50. pp. 6603-6608.
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