Zhao D, Zheng S, Wang X, Liu H, Zhao K, Li L, Hu Y

Hypoxia-inducible factor-1? (HIF-1?) plays central roles in the hypoxia response. It is highly expressed in multiple cancers, but not always correlated with hypoxia. Mutation of the von Hippel-Lindau (VHL) gene, which encodes an E3 ligase, contributes to the constructive activation of HIF-1? in specific tumor types, as exemplified by renal ...

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cell carcinoma; but how VHL wild-type tumors acquire this ability is not completely understood. Here, we found that the oncogene iASPP (inhibitor of apoptosis-simulating protein of p53) plays essential roles in such a context. Genetic inhibition of iASPP reduced tumor growth, accompanied by impaired angiogenesis, increased areas of tumor necrosis, and reduced glycolysis that was HIF-1?-dependent. These abilities of iASPP were validated by in vitro assays. Mechanistically, iASPP directly binds VHL at its ? domain, a region also involved in HIF-1? binding, therefore blocking VHL's binding and the subsequent degradation of HIF-1? protein under normoxia. iASPP levels correlate with HIF-1? protein and vascular endothelial growth factor (VEGF) and the glucose transporter protein type 1(GLUT1), representative HIF-1? target genes, in human colon cancer tissues. Furthermore, inhibition of iASPP expression synergizes with low toxic dose of the HIF-1? inhibitor YC-1 to inhibit HIF-1? expression and tumor growth. Our findings suggest that iASPP contributes to HIF-1? activation in cancers, and that iASPP-mediated HIF-1? stabilization has potential as a therapeutic approach against cancer.

Date: Dec. 01, 2021

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