Sohn Erich J, Libich David S
Greehey Children's Cancer Research Institute and Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Mol Oncol. 2025 Apr;19(4):961-964. doi: 10.1002/1878-0261.13742. Epub 2024 Sep 29.
Ewing sarcoma, an aggressive pediatric cancer, is driven by the EWS::FLI1 fusion protein, which disrupts gene expression by hijacking the BAF chromatin remodeling complex. Central to this mechanism is the formation of biomolecular condensates, mediated by the prion-like domains (PrLDs) of EWS and ARID1A, a core BAF subunit. ARID1A serves as a critical interface between EWS::FLI1 and the BAF complex, with its condensate-forming ability essential for the aberrant gene expression that drives tumor growth. The loss of condensate-competent ARID1A significantly impairs tumor progression, identifying it as a potential therapeutic target. However, targeting condensate formation is challenging due to the transient nature of the interactions involved, complicating the development of effective inhibitors. This work underscores the importance of further investigation into therapeutic strategies aimed at disrupting condensate formation in Ewing sarcoma and other related malignancies.
尤因肉瘤是一种侵袭性儿童癌症，由EWS::FLI1融合蛋白驱动，该蛋白通过劫持BAF染色质重塑复合物来破坏基因表达。这种机制的核心是由EWS和核心BAF亚基ARID1A的朊病毒样结构域（PrLDs）介导的生物分子凝聚物的形成。ARID1A作为EWS::FLI1与BAF复合物之间的关键界面，其形成凝聚物的能力对于驱动肿瘤生长的异常基因表达至关重要。具有凝聚能力的ARID1A的缺失显著损害肿瘤进展，将其确定为一个潜在的治疗靶点。然而，由于所涉及相互作用的短暂性，靶向凝聚物形成具有挑战性，这使得有效抑制剂的开发变得复杂。这项工作强调了进一步研究旨在破坏尤因肉瘤和其他相关恶性肿瘤中凝聚物形成的治疗策略的重要性。
