The hypoxia-inducible factor 1α (HIF-1α) has long been recognized as a key transcription factor to mediate hypoxic effects on tumor growth and progression. By inactivating the canonical function of HIF-1α transcriptional activity, the study by Yoo and colleagues demonstrates that HIF-1α promotes malignant progression via a novel HIF-α-c-Myc pathway of genetic alteration to confer various malignant traits, including epithelial-mesenchymal transition as shown by immunofluorescent staining of E-cadherin (red). Although transduced U-2 OS cells expressing a stabilized HIF-1α lost E-cadherin (2nd row), inactivation of the HIF-1α-c-Myc pathway (3rd row) but not the HIF-1α transcriptional activity (4th row) obliterated HIF-1α-induced epithelialmesenchymal transition. For details, see the article by Yoo and colleagues on page 1244 of this issue.