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

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

  • Oncogene. 2022 Mar;41(13):1944-1958. doi: 10.1038/s41388-022-02234-9.
Dong Zhao 1 Shanliang Zheng 1 Xingwen Wang 1 Hao Liu 1 Kunming Zhao 1 Li Li 2 Ying Hu 3
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China.
  • 2 The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150040, China.
  • 3 School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China. [email protected].
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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