Crucial role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor responsible for the expression of a broad range of genes that facilitate acclimatization to hypoxia. Its stability is predominantly controlled by rapid hydroxylation of two proline residues in its α-subunit. However, how the rapid hydroxylation of HIF-1α is regulated is not fully understood. Here, we report that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1α in human glioma cells under hypoxia. TRPC6 was rapidly activated by IGF-1R-PLCγ-IP3R pathway upon hypoxia. Inhibition of TRPC6 enhanced the levels of α-ketoglutarate and promoted hydroxylation of HIF-1α to suppress HIF-1α accumulation without affecting its transcription or translation. Dimethyloxalylglycine N-(methoxyoxoacetyl)-glycine methyl ester (DMOG), an analog of α-ketoglutarate, reversed the inhibition of HIF-1α accumulation. Moreover, TRPC6 regulated GLUT1 (also known as SLC2A1) expression in a manner that was dependent on HIF-1α accumulation to affect glucose uptake during hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1α stability and consequent glucose metabolism in human glioma cells under hypoxia.

• Authors: Shanshan Li, Jinkui Wang, Yi Wei, Yongjian Liu, Xia Ding, Bin Dong, Yinghui Xu, Yizheng Wang
• Journal: Journal of cell science (J Cell Sci) Vol. 128 Issue 17 Pg. 3317-29 (Sep 01 2015) ISSN: 1477-9137 [Electronic] England
• PMID: 26187851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• TRPC Cation Channels
• TRPC6 Cation Channel
• TRPC6 protein, human
• Glucose

Topics

• Cell Hypoxia
• Cell Line, Tumor
• Glioma (genetics, metabolism, pathology)
• Glucose (genetics, metabolism)
• HEK293 Cells
• Humans
• Hydroxylation (genetics)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Protein Stability
• TRPC Cation Channels (genetics, metabolism)
• TRPC6 Cation Channel