科研之友
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摘要
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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 alpha in specific tumor types, as exemplified by renal 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 alpha-dependent. These abilities of iASPP were validated by in vitro assays. Mechanistically, iASPP directly binds VHL at its beta domain, a region also involved in HIF-1 alpha binding, therefore blocking VHL's binding and the subsequent degradation of HIF-1 alpha protein under normoxia. iASPP levels correlate with HIF-1 alpha protein and vascular endothelial growth factor (VEGF) and the glucose transporter protein type 1(GLUT1), representative HIF-1 alpha target genes, in human colon cancer tissues. Furthermore, inhibition of iASPP expression synergizes with low toxic dose of the HIF-1 alpha inhibitor YC-1 to inhibit HIF-1 alpha expression and tumor growth. Our findings suggest that iASPP contributes to HIF-1 alpha activation in cancers, and that iASPP-mediated HIF-1 alpha stabilization has potential as a therapeutic approach against cancer.
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单位y; 哈尔滨医科大学
