Redox sensor CtBP mediates hypoxia-induced tumor cell migration.
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.
Zhang
Qinghong
Q
Vollum Institute, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. zhangq@ohsu.edu
Wang
Su-Yan
SY
Nottke
Amanda C
AC
Rocheleau
Jonathan V
JV
Piston
David W
DW
Goodman
Richard H
RH
D000429:Alcohol Oxidoreductases; D015374:Biosensing Techniques; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D009243:NAD / Q000378:metabolism; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019289:Pyruvic Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism*
D015820:Cadherins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D009243:NAD; D019289:Pyruvic Acid; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein