PDF(Pubmed)
Abstract：
Ewing\'s sarcoma (ES) represents a rare yet exceedingly aggressive neoplasm that poses a significant health risk to the pediatric and adolescent population. The clinical outcomes for individuals with relapsed or refractory ES are notably adverse, primarily attributed to the constrained therapeutic alternatives available. Despite significant advancements in the field, molecular pathology-driven therapeutic strategies have yet to achieve a definitive reduction in the mortality rates associated with ES. Consequently, there exists an imperative need to discover innovative therapeutic targets to effectively combat ES. To reveal the mechanism of the SETD8 (also known as lysine methyltransferase 5A) inhibitor UNC0379, cell death manners were analyzed with different inhibitors. The contributions of SETD8 to the processes of apoptosis and ferroptosis in ES cells were evaluated employing the histone methyltransferase inhibitor UNC0379 in conjunction with RNA interference techniques. The molecular regulatory mechanisms of SETD8 in ES were examined through the application of RNA sequencing (RNA-seq) and mass spectrometry-based proteomic analysis. Moreover, nude mouse xenograft models were established to explore the role of SETD8 in ES in vivo. SETD8, a sole nucleosome-specific methyltransferase that catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), was found to be upregulated in ES, and its overexpression was associated with dismal outcomes of patients. SETD8 knockdown dramatically induced the apoptosis and ferroptosis of ES cells in vitro and suppressed tumorigenesis in vivo. Mechanistic investigations revealed that SETD8 facilitated the nuclear translocation of YBX1 through post-transcriptional regulatory mechanisms, which subsequently culminated in the transcriptional upregulation of RAC3. In summary, SETD8 inhibits the apoptosis and ferroptosis of ES cells through the YBX1/RAC3 axis, which provides new insights into the mechanism of tumorigenesis of ES. SETD8 may be a potential target for clinical intervention in ES patients.
摘要：
尤因肉瘤（ES）是一种罕见但极具侵袭性的肿瘤，对儿科和青少年人群构成重大健康风险。复发性或难治性ES患者的临床结果明显不利，主要归因于有限的治疗替代方案。尽管在该领域取得了重大进展，分子病理学驱动的治疗策略尚未实现与ES相关的死亡率的最终降低.因此,迫切需要发现创新的治疗靶标以有效对抗ES。为了揭示SETD8(也称为赖氨酸甲基转移酶5A)抑制剂UNC0379的机制,用不同的抑制剂分析细胞死亡方式。使用组蛋白甲基转移酶抑制剂UNC0379结合RNA干扰技术评估了SETD8对ES细胞凋亡和铁凋亡过程的贡献。通过应用RNA测序（RNA-seq）和基于质谱的蛋白质组学分析，检查了ES中SETD8的分子调控机制。此外，建立裸鼠异种移植模型，探讨SETD8在ES中的作用。SETD8，一种唯一的核小体特异性甲基转移酶，催化赖氨酸20处组蛋白H4的单甲基化（H4K20me1），被发现在ES中上调，其过度表达与患者的不良预后相关。SETD8敲低在体外显着诱导ES细胞的凋亡和铁凋亡，并在体内抑制肿瘤发生。机制研究表明，SETD8通过转录后调控机制促进了YBX1的核易位，随后导致RAC3的转录上调。总之,SETD8通过YBX1/RAC3轴抑制ES细胞凋亡和铁凋亡,这为ES的肿瘤发生机制提供了新的见解。SETD8可能是ES患者临床干预的潜在目标。
