Although the up-regulated expression of E-type prostanoid (EP) 4 receptors has been demonstrated during colorectal development, another study showed that the expression levels of EP4 receptors were higher in normal colon tissues than in cancer tissues. To examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities, we here demonstrate that the expression of EP4 receptors is tightly regulated by c-Myc and hypoxia-inducible factor (HIF)-1a by binding to Sp-1 as cellular density-dependently in HCA-7 cells. This tight regulation of EP4 receptor expression by c-Myc and HIF-1a may be an essential system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, it may cause aberrant cellular proliferation, the transformation from normal to cancerous phenotypes, which represents the trigger for the early stage of colorectal carcinogenesis. The present results provide one plausible reason for why conflicting findings exist for the roles of the expression levels of EP4 receptors in carcinogenesis.