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

摘要

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