Stanniocalcin-1 (STC1) is an endocrine hormone originally discovered in the corpuscles of Stannius, endocrine glands on kidneys of bony fishes, and also has been identified in mammals. The mammalian STC1 gene is widely expressed in various tissues and appears to be involved in diverse biological processes. There is growing evidence to suggest that altered patterns of gene expression have a role in human cancer development. Recently STC1 has been identified as a stimulator of mitochondrial respiration and has been hypothesized to be functionally related to the Warburg effect, of which hypoxia-inducible factor (HIF)-1 plays a key role in reprogramming tumor metabolism. This prompted us to examine the involvement of HIF-1 in the regulation of STC1 expression in tumor hypoxia. Our data reveal that hypoxia can stimulate STC1 gene expression in various human cancer cell lines, including those derived from colon carcinomas, nasopharyngeal cancer (CNE-2, HONE-1, HK-1), and ovarian cancer (CaOV3, OVCAR3, SKOV3). By far, the greatest response was observed in CNE-2 cells. In further studies on CNE-2 cells, desferrioxamine, cobalt chloride, and O(2) depletion all increased HIF-1alpha protein and STC1 mRNA levels. Desferrioxamine treatment, when coupled with Fe replenishment, abolished these effects. RNA interference studies further confirmed that endogenous HIF-1alpha was a key factor in hypoxia-induced STC1 expression. The ability of vascular endothelial growth factor to stimulate STC1 expression in CNE-2 cells was comparatively low. Collectively, the present findings provide the first evidence of HIF-1 regulation of STC1 expression in human cancer cells. The studies have implications as to the role of STC1 in hypoxia induced adaptive responses in tumor cells.