Abstract
The rapid growth and poor vascularization of solid tumors expose cancer cells to hypoxia, which promotes the metastatic phenotype by reducing intercellular adhesion and increasing cell motility and invasiveness. In this study, we found that hypoxia increased free NADH levels in cancer cells, promoting CtBP recruitment to the E-cadherin promoter. This effect was blocked by pyruvate, which prevents the NADH increase. Furthermore, hypoxia repressed E-cadherin gene expression and increased tumor cell migration, effects that were blocked by CtBP knockdown. We propose that CtBP senses levels of free NADH to control expression of cell adhesion genes, thereby promoting tumor cell migration under hypoxic stress.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alcohol Oxidoreductases
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Biosensing Techniques*
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Cadherins / genetics
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Cadherins / metabolism
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Cell Movement / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia*
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NAD / metabolism
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Neoplasm Metastasis
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Oxidation-Reduction
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Promoter Regions, Genetic
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Pyruvic Acid / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / metabolism*
Substances
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Cadherins
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DNA-Binding Proteins
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Phosphoproteins
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RNA, Small Interfering
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Repressor Proteins
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NAD
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Pyruvic Acid
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Alcohol Oxidoreductases
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C-terminal binding protein