Abstract PR015: Revealing a novel role for YB-1 as metabolic regulator in Ewing sarcoma

作者：Annalena F. Renner, Fares Burwag, Christopher S. Hughes, Poul H. Sorensen · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.pediatric26-pr015 · 研究领域：Cancer research、Biology、Cell biology、Bioinformatics、Molecular biology

Abstract Metastatic Ewing Sarcoma (EwS) remains a rare but aggressive disease with little to no treatment options available. Therefore, identifying new therapeutic targets is essential. During the establishment of a metastatic niche, sarcoma cells must rapidly adapt to environmental stressors. They achieve this by stalling translation complexes and accumulating mRNA along with RNA-binding proteins in structures known as Stress Granules (SGs). The essential SG protein Y-Box binding protein 1 (YB-1) is highly expressed in EwS and is associated with poor patient outcomes. Previous work from our lab demonstrated that YB-1 contributes to tumor progression and growth. New multi-omics data on EwS cells correlates with these findings and revealed a role for YB-1 in mitochondrial control in these high-risk sarcomas, specifically in regulating electron transport chain (ETC) complexes and possibly mitochondrial translation. We hypothesize that YB-1 interferes with mitochondrial function in EwS. We discovered that under oxidative stress as expected many metabolic pathways are downregulated in a EwS polysome sequencing dataset we generated, when compared with a YB-1 RNA interaction dataset we could identify less binding of ETC complex I and IV transcripts to YB-1 under oxidative stress as well. This was particularly interesting since many of those genes are transcribed and translated in the mitochondria. A transient knockdown of YB-1 increased levels of ROS, as well as mitochondrial super...