To identify genes differentially expressed under normoxic (21% O(2)) or hypoxic (1% O(2)) conditions, we used the technique of mRNA differential display using total RNA extracted from Chang human liver cells. Among downregulated genes by hypoxia, we focused on hHR21(SP) (human homologue of rad21 S. pombe) that is involved in DNA double-strand break repair. Northern blot analysis revealed that mRNA expression of hHR21(SP) was inhibited by hypoxia in various tumor cell lines, such as HepG2, SKHep1, MCF7, and HT1080 cells. We also found that hypoglycemia and heat shock significantly decreased the hHR21(SP) level, indicating that a DNA double-strand break repair gene, hHR21(SP) might be regulated by environmental stresses. In addition, wortmannin, a DNA-dependent protein kinase (DNA-PK) inhibitor, decreased the level of hHR21(SP) mRNA, indicating that DNA-PK might be involved in the regulation of hHR21(SP). These results propose a new understanding of hHR21(SP) regulations in human tumor cells.