A positive feedback circuit comprising p21 and HIF‐1α aggravates hypoxia‐induced radioresistance of glioblastoma by promoting Glut1/LDHA‐mediated glycolysis
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...
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| Veröffentlicht in: | The FASEB journal 2022-03, Vol.36 (3), p.e22229-n/a |
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| creator | Jin, Xiaodong Kuang, Yanbei Li, Linying Li, Hongbin Zhao, Ting He, Yufang Di, Cuixia Kang, Jian Yuan, Lingyan Yu, Boyi Li, Qiang |
| description | 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. |
| doi_str_mv | 10.1096/fj.202101736R |
| format | Article |
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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.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.202101736R</identifier><identifier>PMID: 35199870</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Brain Neoplasms - metabolism ; Brain Neoplasms - radiotherapy ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Feedback, Physiological ; Female ; glioblastoma ; Glioblastoma - metabolism ; Glioblastoma - radiotherapy ; Glucose Transporter Type 1 - metabolism ; Glycolysis ; HIF‐1α ; Humans ; hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; L-Lactate Dehydrogenase - metabolism ; Mice ; p21 ; Radiation Tolerance ; radioresistance ; Tumor Hypoxia</subject><ispartof>The FASEB journal, 2022-03, Vol.36 (3), p.e22229-n/a</ispartof><rights>2022 Federation of American Societies for Experimental Biology</rights><rights>2022 Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3389-8919a6d1d3a9d2019280e3404719fefcc5921cc8b7eb15bb54818a7977e1fa733</citedby><cites>FETCH-LOGICAL-c3389-8919a6d1d3a9d2019280e3404719fefcc5921cc8b7eb15bb54818a7977e1fa733</cites><orcidid>0000-0001-8043-9205</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.202101736R$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.202101736R$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35199870$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jin, Xiaodong</creatorcontrib><creatorcontrib>Kuang, Yanbei</creatorcontrib><creatorcontrib>Li, Linying</creatorcontrib><creatorcontrib>Li, Hongbin</creatorcontrib><creatorcontrib>Zhao, Ting</creatorcontrib><creatorcontrib>He, Yufang</creatorcontrib><creatorcontrib>Di, Cuixia</creatorcontrib><creatorcontrib>Kang, Jian</creatorcontrib><creatorcontrib>Yuan, Lingyan</creatorcontrib><creatorcontrib>Yu, Boyi</creatorcontrib><creatorcontrib>Li, Qiang</creatorcontrib><title>A positive feedback circuit comprising p21 and HIF‐1α aggravates hypoxia‐induced radioresistance of glioblastoma by promoting Glut1/LDHA‐mediated glycolysis</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>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. 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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.</description><subject>Animals</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - radiotherapy</subject><subject>Cell Line, Tumor</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Feedback, Physiological</subject><subject>Female</subject><subject>glioblastoma</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - radiotherapy</subject><subject>Glucose Transporter Type 1 - metabolism</subject><subject>Glycolysis</subject><subject>HIF‐1α</subject><subject>Humans</subject><subject>hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>Mice</subject><subject>p21</subject><subject>Radiation Tolerance</subject><subject>radioresistance</subject><subject>Tumor Hypoxia</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtu1EAQhlsIRIbAki3qJRsn_Rj3YzmETCbSSEg81la7u3rowXYbtx3iHUfgDpyAi3CInCQ9mgA7alOL-vSpqn6EXlJyRokW535_xgijhEou3j9CC1pyUgglyGO0IEqzQgiuTtCzlPaEkMyJp-iEl1RrJckC_VzhPqYwhhvAHsDVxn7BNgx2CiO2se2HkEK3wz2j2HQOb67Xd99_0N-_sNntBnNjRkj489zH22DyIHRusuDwYFyIA6SQRtNZwNHjXRNi3Zg0xtbgesb9ENs4HtxXzTTS8-3bzSobWnAhS13mZxubOSueoyfeNAlePPRT9Gl9-fFiU2zfXV1frLaF5VzpQmmqjXDUcaMdI1QzRYAvyVJS7cFbW2pGrVW1hJqWdV0uFVVGaimBeiM5P0Wvj9682tcJ0li1IVloGtNBnFLFBGdSaybKjBZH1A4xpQF8lR_VmmGuKKkOuVR-X_3LJfOvHtRTnS_8S_8JIgPLI_AtNDD_31atP7xhh9L8HlqSni8</recordid><startdate>202203</startdate><enddate>202203</enddate><creator>Jin, Xiaodong</creator><creator>Kuang, Yanbei</creator><creator>Li, Linying</creator><creator>Li, Hongbin</creator><creator>Zhao, Ting</creator><creator>He, Yufang</creator><creator>Di, Cuixia</creator><creator>Kang, Jian</creator><creator>Yuan, Lingyan</creator><creator>Yu, Boyi</creator><creator>Li, Qiang</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8043-9205</orcidid></search><sort><creationdate>202203</creationdate><title>A positive feedback circuit comprising p21 and HIF‐1α aggravates hypoxia‐induced radioresistance of glioblastoma by promoting Glut1/LDHA‐mediated glycolysis</title><author>Jin, Xiaodong ; Kuang, Yanbei ; Li, Linying ; Li, Hongbin ; Zhao, Ting ; He, Yufang ; Di, Cuixia ; Kang, Jian ; Yuan, Lingyan ; Yu, Boyi ; Li, Qiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3389-8919a6d1d3a9d2019280e3404719fefcc5921cc8b7eb15bb54818a7977e1fa733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - radiotherapy</topic><topic>Cell Line, Tumor</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Feedback, Physiological</topic><topic>Female</topic><topic>glioblastoma</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - radiotherapy</topic><topic>Glucose Transporter Type 1 - metabolism</topic><topic>Glycolysis</topic><topic>HIF‐1α</topic><topic>Humans</topic><topic>hypoxia</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>L-Lactate Dehydrogenase - metabolism</topic><topic>Mice</topic><topic>p21</topic><topic>Radiation Tolerance</topic><topic>radioresistance</topic><topic>Tumor Hypoxia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jin, Xiaodong</creatorcontrib><creatorcontrib>Kuang, Yanbei</creatorcontrib><creatorcontrib>Li, Linying</creatorcontrib><creatorcontrib>Li, Hongbin</creatorcontrib><creatorcontrib>Zhao, Ting</creatorcontrib><creatorcontrib>He, Yufang</creatorcontrib><creatorcontrib>Di, Cuixia</creatorcontrib><creatorcontrib>Kang, Jian</creatorcontrib><creatorcontrib>Yuan, Lingyan</creatorcontrib><creatorcontrib>Yu, Boyi</creatorcontrib><creatorcontrib>Li, Qiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jin, Xiaodong</au><au>Kuang, Yanbei</au><au>Li, Linying</au><au>Li, Hongbin</au><au>Zhao, Ting</au><au>He, Yufang</au><au>Di, Cuixia</au><au>Kang, Jian</au><au>Yuan, Lingyan</au><au>Yu, Boyi</au><au>Li, Qiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A positive feedback circuit comprising p21 and HIF‐1α aggravates hypoxia‐induced radioresistance of glioblastoma by promoting Glut1/LDHA‐mediated glycolysis</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2022-03</date><risdate>2022</risdate><volume>36</volume><issue>3</issue><spage>e22229</spage><epage>n/a</epage><pages>e22229-n/a</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><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. 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| ispartof | The FASEB journal, 2022-03, Vol.36 (3), p.e22229-n/a |
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| language | eng |
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| source | Wiley-Blackwell Journals; MEDLINE; Alma/SFX Local Collection |
| subjects | Animals Brain Neoplasms - metabolism Brain Neoplasms - radiotherapy Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Feedback, Physiological Female glioblastoma Glioblastoma - metabolism Glioblastoma - radiotherapy Glucose Transporter Type 1 - metabolism Glycolysis HIF‐1α Humans hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism L-Lactate Dehydrogenase - metabolism Mice p21 Radiation Tolerance radioresistance Tumor Hypoxia |
| title | A positive feedback circuit comprising p21 and HIF‐1α aggravates hypoxia‐induced radioresistance of glioblastoma by promoting Glut1/LDHA‐mediated glycolysis |
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