ARID1A与EWS::FLI1在尤文肉瘤中机制性相互作用：BAF复合物的劫持

Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma

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Molecular Oncology

影响因子:4.5

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

DOI: 10.1002/1878-0261.13742

摘要

尤文肉瘤是一种侵袭性儿童癌症，由EWS::FLI1融合蛋白驱动，该融合蛋白通过劫持BAF染色质重塑复合物来破坏基因表达。其核心机制涉及由EWS和ARID1A的prion样结构域（PrLDs）介导的生物分子凝聚体的形成。ARID1A作为EWS::FLI1与BAF复合体之间的关键接口，其凝聚体形成能力对于驱动肿瘤生长的异常基因表达至关重要。缺失具有凝聚能力的ARID1A显著抑制肿瘤进展，提示其为潜在的治疗靶点。然而，靶向凝聚体形成具有挑战性，因为涉及的相互作用具有短暂性，增加了有效抑制剂开发的难度。本文强调需要深入研究针对破坏尤文肉瘤及相关恶性肿瘤中凝聚体形成的治疗策略。

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.