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iASPP is essential for HIF-1α stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation

Oncogene volume 41, pages 1944–1958 (2022)Cite this article

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) 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-1α 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-1α-dependent. These abilities of iASPP were validated by in vitro assays. Mechanistically, iASPP directly binds VHL at its β domain, a region also involved in HIF-1α binding, therefore blocking VHL’s binding and the subsequent degradation of HIF-1α protein under normoxia. iASPP levels correlate with HIF-1α protein and vascular endothelial growth factor (VEGF) and the glucose transporter protein type 1(GLUT1), representative HIF-1α target genes, in human colon cancer tissues. Furthermore, inhibition of iASPP expression synergizes with low toxic dose of the HIF-1α inhibitor YC-1 to inhibit HIF-1α expression and tumor growth. Our findings suggest that iASPP contributes to HIF-1α activation in cancers, and that iASPP-mediated HIF-1α stabilization has potential as a therapeutic approach against cancer.

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Fig. 1: Inhibiting iASPP expression attenuates tumor growth through HIF-1ɑ signaling.
Fig. 2: iASPP activates HIF-1α-dependent pro-tumorigenic signals.
Fig. 3: iASPP promotes the transcriptional activity of HIF-1ɑ.
Fig. 4: iASPP stabilizes HIF-1α protein.
Fig. 5: iASPP prevents HIF-1α degradation by interfering with the VHL/PHD pathway.
Fig. 6: iASPP directly binds with VHL and prevents HIF-1α degradation.
Fig. 7: HIF-1α, iASPP, and VEGF expression are positively correlated in human clinical samples.
Fig. 8: iASPP inhibition increases tumor sensitivity to the HIF-1α inhibitor YC-1.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (No. 82025027, 31871389, 31741084, 32000517), China Postdoctoral Science Foundation (No. 2020M680045 and 2021T140161), and the Nature Science Foundation of Heilongjiang Province (No. YQ2021C024).

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  1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China

    Dong Zhao, Shanliang Zheng, Xingwen Wang, Hao Liu, Kunming Zhao & Ying Hu

  2. The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150040, China

    Li Li

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YH designed the experiments and wrote the paper. DZ, SZ, XW, performed the experiments and analyzed the data. KZ generated shHIF-1α plasmids. HL was responsible for animal feeding and experimentation. LL collected clinical COAD samples.

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Correspondence to Ying Hu.

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Zhao, D., Zheng, S., Wang, X. et al. iASPP is essential for HIF-1α stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation. Oncogene 41, 1944–1958 (2022). https://doi.org/10.1038/s41388-022-02234-9

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