[{"key":"dc.contributor.author","value":"Long, Justin David","language":null},{"key":"dc.date.accessioned","value":"2026-04-24T20:38:35Z","language":null},{"key":"dc.date.available","value":"2026-04-24T20:38:36Z","language":null},{"key":"dc.date.issued","value":"2026","language":"en"},{"key":"dc.identifier.uri","value":"http:\/\/hdl.handle.net\/2429\/94211","language":null},{"key":"dc.description.abstract","value":"Ewing sarcoma (EwS) is an aggressive type of bone cancer that disproportionately affects \r\nchildren and young adults. EwS is characterized by a chromosomal translocation that produces a \r\nde novo oncofusion between members of the FET-ETS gene families. The two most commonly \r\nidentified gene fusions in EwS are EWSR1::FLI1 (EWS::FLI1) and EWS::ERG, in which their \r\nrespective proteins bind to GGAA repeat sequences to induce or repress enhancers acting as an \r\naberrant transcription factor and rewiring transcriptional programs essential for tumor \r\ndevelopment. Understanding the function of dysregulated genes is crucial for developing \r\ntargeted treatments in EwS. I recently identified that a novel truncated isoform of DLG2 is highly \r\nexpressed in EwS with no prior characterization in cancer. \r\nI identified that EwS is among the highest DLG2 expressing cancers, and more specifically, \r\nthat EwS expresses a truncated isoform of DLG2, identified as DLG2\u03b73, likely through a de novo \r\nenhancer bound by EWS::FLI1. Based on H3K27Ac data, I observed that the DLG2\u03b73 gene locus is \r\nthe third strongest super enhancer only when EWS::FLI1 is expressed, supporting a direct role of \r\nEWS::FLI1 in inducing DLG2\u03b73 gene expression. Additionally, I showed that DLG2\u03b73 mRNA and \r\nprotein can be altered depending on the availability of free intracellular iron. I then showed that \r\nDLG2\u03b73 mRNA contains two likely iron responsive elements, suggesting an iron-dependent \r\ntranslational control mechanism. \r\nI wanted to identify if DLG2\u03b73 contributed to the oncogenic phenotype of EwS. Here, I \r\nshowed that DLG2\u03b73-depleted EwS cells are less capable of forming 3D growth in both in vitro \r\nand in vivo model systems. To determine the oncogenic role of DLG2\u03b73, I assessed the relationship \r\nbetween DLG2\u03b73, iron, and survival in EwS cells. Not only did DLG2\u03b73-depleted EwS cells show \r\nan increase in mitochondrial superoxides, but there was also an apparent increase in lipid \r\nperoxide levels and cell death under ambient and high iron conditions in comparison to control \r\ncells. Addition of ferrostatin-1 entirely rescued the observed phenotype, suggesting that DLG2\u03b73\r\ndepleted cells are entering ferroptosis at higher rates.  \r\nCollectively, this data profiles the pro-tumorigenic role of DLG2\u03b73 and its potential \r\ndownstream involvement in ferroptosis protection in Ewing sarcoma.","language":"en"},{"key":"dc.language.iso","value":"eng","language":"en"},{"key":"dc.publisher","value":"University of British Columbia","language":"en"},{"key":"dc.rights","value":"Attribution-NoDerivatives 4.0 International","language":"*"},{"key":"dc.rights.uri","value":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/","language":"*"},{"key":"dc.title","value":"Investigating mechanistic roles of a novel onco-fusion-driven transcript isoform, named DLG2\u03b73, in Ewing sarcoma","language":"en"},{"key":"dc.type","value":"Text","language":"en"},{"key":"dc.degree.name","value":"Master of Science - MSc","language":"en"},{"key":"dc.degree.discipline","value":"Interdisciplinary Oncology","language":"en"},{"key":"dc.degree.grantor","value":"University of British Columbia","language":"en"},{"key":"dc.contributor.supervisor","value":"Sorensen, Poul H.","language":null},{"key":"dc.date.graduation","value":"2026-11","language":"en"},{"key":"dc.type.text","value":"Thesis\/Dissertation","language":"en"},{"key":"dc.description.affiliation","value":"Medicine, Faculty of","language":"en"},{"key":"dc.degree.campus","value":"UBCV","language":"en"},{"key":"dc.description.scholarlevel","value":"Graduate","language":"en"}]