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

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.

• Authors: Dong Zhao, Shanliang Zheng, Xingwen Wang, Hao Liu, Kunming Zhao, Li Li, Ying Hu
• Journal: Oncogene (Oncogene) Vol. 41 Issue 13 Pg. 1944-1958 (03 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35169254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intracellular Signaling Peptides and Proteins
• PPP1R13L protein, human
• Repressor Proteins
• Vascular Endothelial Growth Factor A
• Ubiquitin-Protein Ligases
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Glycolysis
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Kidney Neoplasms (genetics, metabolism)
• Neovascularization, Pathologic (genetics)
• Proteolysis
• Repressor Proteins (genetics, metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)