Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 509, Issue 1, Pages 1-8Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2011.02.011
Keywords
Glyceraldehyde-3-phosphate dehydrogenase; Hypoxia-inducible factor-1; Breast cancer; Transcription factor; Hypoxia response element; Sp1
Categories
Funding
- Japan Society for the Promotion of Science [20580141, 21-5864]
- Grants-in-Aid for Scientific Research [20580141, 22249016] Funding Source: KAKEN
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Hypoxia up-regulates the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a cell type-specific manner. It is unknown whether this occurs in breast cancer. Here, we report that hypoxia up-regulates the GAPDH gene expression through breast cancer-specific molecular mechanisms in MCF-7 cells. Mutation analysis identified a novel hypoxia response element (HRE), in addition to the HRE found previously in prostate cancer LNCaP cells. Knockdown and overexpression of hypoxia-inducible factor (HIF)-1 alpha indicated that HIF-1 contributed to the up-regulation of GAPDH gene expression by hypoxia. Although chromatin immunoprecipitation (ChIP) and plasmid immunoprecipitation analyses revealed the presence of HIF-1 alpha on the novel HRE in both hypoxic cell lines, a mutation in either the novel HRE or its 3'-flanking GC-box resulted in a reduction of hypoxia-increased GAPDH promoter activity only in MCF-7 cells. ChIP analysis showed that Sp1 bound to the GC-box in MCF-7 cells, but not in LNCaP cells, in normoxia and hypoxia. Knockdown of Sp1 reduced hypoxia-increased promoter activity and expression level of GAPDH in MCF-7 cells. These results indicate that in MCF-7 cells, the activation of HIF-1 on the novel HRE contributes to the breast cancer-specific hypoxic induction of GAPDH gene expression and absolutely depends on the presence of Sp1 on the GC-box. (C) 2011 Elsevier Inc. All rights reserved.
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