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

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

  • J Cell Sci. 2015 Sep 1;128(17):3317-29. doi: 10.1242/jcs.173161.
Shanshan Li 1 Jinkui Wang 2 Yi Wei 2 Yongjian Liu 2 Xia Ding 1 Bin Dong 3 Yinghui Xu 3 Yizheng Wang 4
Affiliations

Affiliations

  • 1 Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
  • 3 Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China [email protected] [email protected] [email protected].
  • 4 Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China [email protected] [email protected] [email protected].
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.

Keywords

GLUT1; HIF-1α; Hypoxia; TRPC6; α-Ketoglutarate.

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