Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme

• Type of Material: Article
• Authors: Robyn A Umans, The Fralin Biomedical Research Institute at VTC; Joelle Martin, The Fralin Biomedical Research Institute at VTC; Dipan Patel, Emory University; Megan E Harrigan, The Fralin Biomedical Research Institute at VTC; Lata Chaunsali, University of Virginia; Aarash Roshandel, Virginia Polytechnic Institute and State University; Kavya Iyer, Roanoke College; Michael D Powell, Emory University; Ken Oestreich, Ohio State University; Harald Sontheimer, University of Virginia
• Language: English
• Date: 2021-12-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers13246169
• Title of Journal or Parent Work: CANCERS
• Volume: 13
• Issue: 24
• Grant/Funding Information: This research was funded by The National Institutes of Health, grant number 1R01CA227149-01A1.
• Keywords: PRIMARY BRAIN; glutamate; Oncology; SULFASALAZINE; MUTANT P53; GLIOMA; CANCER; Life Sciences & Biomedicine; p53; RELEASE; Science & Technology; SYSTEM X(C)(-); glioblastoma multiforme

Abstract

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 SLC7A11, 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 SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 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-1Met, 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.