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

Oncogene volume 29, pages 6603–6608 (2010)Cite this article

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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.

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Acknowledgements

This work was supported by Grants from the NIH, R01DE15953 (to X-JW) and R01CA115468 (to QZ). We thank Dr Petra Boukamp for providing the normal human keratinocytes HaCaT cells and Dr James Mitchell for helpful discussions.

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Authors and Affiliations

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

    Y Deng, J Liu & Q Zhang

  2. Department of Pathology, University of Colorado, Denver, Aurora, CO, USA

    G Han & X-J Wang

  3. Department of Otolaryngology, University of Colorado, Denver, Aurora, CO, USA

    S-L Lu

  4. Vollum Institute, Oregon Health & Science University, Portland, OR, USA

    S-Y Wang

  5. Department of Medicine, Pulmonary Division, University of Colorado, Denver, Aurora, CO, USA

    S Malkoski

  6. Department of Medicine, Medical Oncology Division, University of Colorado, Denver, Aurora, CO, USA

    A C Tan

  7. NIDDK, National Institutes of Health, Bethesda, MD, USA

    C Deng

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Correspondence to X-J Wang or Q Zhang.

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Deng, Y., Liu, J., Han, G. et al. Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. Oncogene 29, 6603–6608 (2010). https://doi.org/10.1038/onc.2010.406

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