Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme
Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of <i>SLC7A11</i>, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/24/6169 |
| _version_ | 1797506355310886912 |
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| author | Robyn A. Umans Joelle Martin Megan E. Harrigan Dipan C. Patel Lata Chaunsali Aarash Roshandel Kavya Iyer Michael D. Powell Ken Oestreich Harald Sontheimer |
| author_facet | Robyn A. Umans Joelle Martin Megan E. Harrigan Dipan C. Patel Lata Chaunsali Aarash Roshandel Kavya Iyer Michael D. Powell Ken Oestreich Harald Sontheimer |
| author_sort | Robyn A. Umans |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of <i>SLC7A11</i>, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the <i>SLC7A11</i> promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases <i>SLC7A11</i> transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1<sup>Met</sup>, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility. |
| first_indexed | 2024-03-10T04:31:29Z |
| format | Article |
| id | doaj.art-157ab1de9b074665b6c0270cc369f118 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:31:29Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-157ab1de9b074665b6c0270cc369f1182023-11-23T04:04:41ZengMDPI AGCancers2072-66942021-12-011324616910.3390/cancers13246169Transcriptional Regulation of Amino Acid Transport in Glioblastoma MultiformeRobyn A. Umans0Joelle Martin1Megan E. Harrigan2Dipan C. Patel3Lata Chaunsali4Aarash Roshandel5Kavya Iyer6Michael D. Powell7Ken Oestreich8Harald Sontheimer9Center for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USACenter for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USACenter for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USADepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USADepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USACollege of Agriculture and Life Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USARoanoke College, Salem, VA 24153, USADepartment of Microbiology and Immunity, Emory University School of Medicine, Atlanta, GA 30322, USAMicrobial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH 43210, USADepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USAGlioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of <i>SLC7A11</i>, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the <i>SLC7A11</i> promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases <i>SLC7A11</i> transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1<sup>Met</sup>, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.https://www.mdpi.com/2072-6694/13/24/6169glioblastoma multiformeSLC7A11p53glutamate |
| spellingShingle | Robyn A. Umans Joelle Martin Megan E. Harrigan Dipan C. Patel Lata Chaunsali Aarash Roshandel Kavya Iyer Michael D. Powell Ken Oestreich Harald Sontheimer Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme Cancers glioblastoma multiforme SLC7A11 p53 glutamate |
| title | Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme |
| title_full | Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme |
| title_fullStr | Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme |
| title_full_unstemmed | Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme |
| title_short | Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme |
| title_sort | transcriptional regulation of amino acid transport in glioblastoma multiforme |
| topic | glioblastoma multiforme SLC7A11 p53 glutamate |
| url | https://www.mdpi.com/2072-6694/13/24/6169 |
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