Hypoxia-inducible factor 1α mediates the down-regulation of superoxide dismutase 2 in von Hippel–Lindau deficient renal clear cell carcinoma

• VHL up-regulates SOD2 expression on mRNA and protein levels.
• HIF-1α contributes to the transcriptional suppression of SOD2 expression in the pVHL deficient cells.
• HIF-1α directly binds the hypoxia-responsive element of SOD2 promoter.
• The expression of HIF-1α negatively correlates with SOD2 expression in pVHL deficient renal clear cell carcinoma tissues.

Hypoxia-inducible factor 1α (HIF-1α) is an oxygen-sensitive subunit of HIF-1, the master transcription factor for cellular response to hypoxia. Down-regulation of the mitochondrial enzyme superoxide dismutase 2 (SOD2) contributes to the stabilization of HIF-1α under hypoxia due to the decreased dismutation of superoxide radical. Here we report that HIF-1α could also regulate the expression of SOD2. We found that both stabilization of HIF-1α expression under nomoxia caused by pVHL deficiency and hypoxia treatment significantly reduced SOD2 expression, and shRNAs specifically against HIF-1α restored SOD2 expression in both circumstances. Further analyses with luciferase reporter assay and chromatin immunoprecipitation assay revealed that HIF-1α inhibited and directly bound to the hypoxia-responsive element in SOD2 promoter. These findings indicated the existence of a positive feedback between HIF-1α and SOD2 and provided new clues for understanding the molecular mechanisms of hypoxia adaptation.