劫持BAF综合体：ARID1A和EWS的机械相互作用:: fli1在Ewing Sarmom中
Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma
影响因子:4.50000
分区:医学2区 / 肿瘤学3区
发表日期:2025 Apr
作者:
Erich J Sohn, David S Libich
摘要
Ewing肉瘤是一种侵略性的小儿癌，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。这种机制的核心是生物分子冷凝物的形成，由核心BAF亚基的EWS和ARID1A的Prion样域（PRLD）介导。 ARID1A是EWS :: FLI1和BAF复合物之间的关键界面，其冷凝物形成能力对于驱动肿瘤生长的异常基因表达至关重要。凝聚力的ARID1A的丧失显着损害了肿瘤的进展，从而将其视为潜在的治疗靶点。但是，由于所涉及的相互作用的短暂性质，靶向冷凝物的形成具有挑战性，这使有效抑制剂的发展变得复杂。这项工作强调了对旨在破坏尤因肉瘤和其他相关恶性肿瘤中冷凝物形成的治疗策略进一步研究的重要性。
Abstract
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.