A positive feedback circuit comprising p21 and HIF-1α aggravates hypoxia-induced radioresistance of glioblastoma by promoting Glut1/LDHA-mediated glycolysis.

Abstract

The radioresistance induced by hypoxia is the major obstacle in the successful treatment of cancer radiotherapy. p21 was initially identified as a widespread inhibitor of cyclin-dependent kinases, through which mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. In this study, we discovered a novel function of p21, which participated in the regulation of metabolic pathways under hypoxia. We found that p21 was upregulated in glioblastoma (GBM) cells under hypoxic conditions, which enhanced the radioresistance of GBM cells. In principle, HIF-1α is bound directly to the hypoxia response elements (HREs) of the p21 promoter to enhance its transcription activity, in turn, p21 also promoted the transcription of HIF-1α at the mRNA level and maintained HIF-1α function under oxygen deficiency. The positive correlation between p21 and HIF-1α augmented Glut1/LDHA-mediated glycolysis and aggravated the radioresistance of GBM cells. Thus, our results constructed a positive feedback circuit comprising p21/HIF-1α that might play a key role in enhancing the radioresistance of GBM under hypoxia.

• Authors: Xiaodong Jin, Yanbei Kuang, Linying Li, Hongbin Li, Ting Zhao, Yufang He, Cuixia Di, Jian Kang, Lingyan Yuan, Boyi Yu, Qiang Li
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 3 Pg. e22229 (03 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 35199870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Federation of American Societies for Experimental Biology.

Chemical References

• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Glucose Transporter Type 1
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Slc2a1 protein, mouse
• L-Lactate Dehydrogenase

Topics

• Animals
• Brain Neoplasms (metabolism, radiotherapy)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Feedback, Physiological
• Female
• Glioblastoma (metabolism, radiotherapy)
• Glucose Transporter Type 1 (metabolism)
• Glycolysis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Mice
• Radiation Tolerance
• Tumor Hypoxia