Constitutive HIF-1 activity in malignant melanoma

Abstract

The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1beta and the oxygen-responsive HIF-1alpha subunit, is the master activator of the cellular transcriptional response to hypoxia coordinating gene expression during reduced oxygen tension. Overexpression of HIF-1 and increased transcriptional activity induced by hypoxia are linked to progression of many tumour types such as head and neck cancer, cervical carcinoma, leukaemia and renal cell carcinoma. In this study, we demonstrate that HIF activity is increased in malignant melanoma cells already under normoxic conditions in contrast to other tumour types. HIF-1alpha and -2alpha knockdown by siRNA transfection revealed that this effect is due to constitutive HIF-1alpha expression. Furthermore, the inhibition or activation of reactive oxygen species (ROS) decreased or activated, respectively, HIF-1 activity and HIF-1alpha protein expression. Interestingly, the inhibition of the NFkappaB pathway also reduced the accumulation of HIF-1alpha assuming a context between ROS and NFkappaB, and suggesting that ROS and NFkappaB activity contribute to HIF-1alpha accumulation. In summary, we identified an increased HIF-1alpha protein expression and activity in melanoma under normoxia mediated by ROS and the NFkappaB pathway.