title: 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.affiliation: 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Jinkui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China yzwang@ion.ac.cn xuyh_dl@126.com stocktondb@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Neurosurgery, 1st Affiliated Hospital of Dalian Medical University, Dalian 116011, China yzwang@ion.ac.cn xuyh_dl@126.com stocktondb@163.com.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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 yzwang@ion.ac.cn xuyh_dl@126.com stocktondb@163.com.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D005947:Glucose
keywords: GLUT1; HIF-1α; Hypoxia; TRPC6; α-Ketoglutarate