Department of Oncology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, No. 107 Yanjiang Road, Guangzhou, 510120, China.
Department of Clinical Laboratory, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Cell Death Dis. 2024 Jul 10;15(7):494. doi: 10.1038/s41419-024-06882-5.
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.
尤因氏肉瘤 (ES) 是一种罕见但极具侵袭性的肿瘤，对儿童和青少年群体构成重大健康威胁。复发或难治性 ES 患者的临床结局明显不佳，主要归因于可用的治疗选择有限。尽管在该领域取得了重大进展，但基于分子病理学的治疗策略尚未能显著降低 ES 相关死亡率。因此，迫切需要发现创新的治疗靶点来有效对抗 ES。为了揭示 SETD8（也称为赖氨酸甲基转移酶 5A）抑制剂 UNC0379 的作用机制，用不同的抑制剂分析细胞死亡方式。通过使用组蛋白甲基转移酶抑制剂 UNC0379 结合 RNA 干扰技术，评估 SETD8 对 ES 细胞凋亡和铁死亡过程的贡献。通过应用 RNA 测序 (RNA-seq) 和基于质谱的蛋白质组学分析，研究 SETD8 在 ES 中的分子调控机制。此外，建立裸鼠异种移植模型以在体内探索 SETD8 在 ES 中的作用。SETD8 是一种唯一的核小体特异性甲基转移酶，催化组蛋白 H4 赖氨酸 20 单甲基化 (H4K20me1)，在 ES 中上调，其过表达与患者预后不良相关。SETD8 敲低显著诱导 ES 细胞体外凋亡和铁死亡，并抑制体内肿瘤发生。机制研究表明，SETD8 通过转录后调节机制促进 YBX1 的核转位，进而导致 RAC3 的转录上调。总之，SETD8 通过 YBX1/RAC3 轴抑制 ES 细胞的凋亡和铁死亡，为 ES 肿瘤发生的机制提供了新的见解。SETD8 可能是 ES 患者临床干预的潜在靶点。
