STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is rapidly degraded by the ubiquitin-proteasome pathway under normoxic conditions. Ubiquitination of HIF-1 alpha is mediated by interaction with von Hippel-Lindau tumor suppressor protein (pVHL). In our previous report, we found that hypoxia-induced active signal transducer and activator of transcription3 (STAT3) accelerated the accumulation of HIF-1 alpha protein and prolonged its half-life in solid tumor cells. However, its specific mechanisms are not fully understood. Thus, we examined the role of STAT3 in the mechanism of pVHL-mediated HIF-1 alpha stability. We found that STAT3 interacts with C-terminal domain of HIF-1 alpha and stabilizes HIF-1 alpha by inhibition of pVHL binding to HIF-1 alpha. The binding between HIF-1 alpha and pVHL, negative regulator of HIF-1 alpha stability, was interfered dose-dependently by overexpressed constitutive active STAT3. Moreover, we found that the enhanced HIF-1 alpha protein levels by active STAT3 are due to decrease of poly-ubiquitination of HIF-1 alpha protein via inhibition of interaction between pVHL and HIF-1 alpha. Taken together, our results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1 alpha through competition with pVHL for binding to HIF-1 alpha, and then stabilizes HIF-1 alpha protein levels.