Critical 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 transcriptional 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 prolines on 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 in hypoxia. Inhibition of TRPC6 enhanced the levels of α-ketoglutarate (α-KG) 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-KG, reversed the inhibition of HIF-1α accumulation. Moreover, TRPC6 regulated GLUT1 expression depending on HIF-1α accumulation to affect glucose uptake in hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1α stability and consequent glucose metabolism in human glioma cells under hypoxia.