横纹肌肉瘤（RMS）主要是儿科肉瘤，被认为起源于由于肌原性分化受损而产生的肌肉前体细胞。尽管进行了强化治疗，晚期疾病患者的 5 年生存率仍然很低（< 30%），这突出表明需要新的疗法来改善预后。分化治疗剂是诱导癌细胞从恶性分化为良性的药物。组蛋白甲基转移酶、Zeste 同源物增强剂 2 (EZH2) 抑制正常骨骼肌分化，并在 RMS 肿瘤中高表达。我们证明，将表观遗传调节剂 EZH2 的抑制与分化剂视黄酸 (RA) 相结合，可以更有效地减少细胞增殖在 RMS 细胞系中的效果优于单独使用单一药物。在 PAX3-FOXO1 阳性 RMS 细胞中，这是由于 RA 驱动的干扰素途径诱导导致细胞凋亡。在融合阴性 RMS 中，联合治疗导致 EZH2i 驱动的肌源信号上调，从而导致分化。在这两种亚型中，EZH2 与组蛋白 3 (H3K27me3) 基因上的三甲基化赖氨酸 27 的富集显着相关，这些基因在未经处理的 RMS 细胞中下调，而在 EZH2 抑制剂处理下上调。这些结果深入了解了 EZH2/RA 单药和联合治疗的抗癌作用机制，并表明 EZH2 活性的降低与 RA 信号传导的诱导相结合代表了治疗两种亚型癌症的潜在新治疗策略。 RMS。这项研究的结果证明了 EZH2 抑制剂与分化剂联合治疗儿童横纹肌肉瘤的潜在效用。由于 EZH2 抑制剂目前正在进行成人和儿童实体瘤的临床试验，并且视黄酸分化剂已经在临床使用，这提供了一种易于转化的潜在治疗策略。此外，由于在预后不良的 FPRMS 亚型中抑制 EZH2 会导致炎症反应，因此可以想象，该策略也可能与免疫疗法协同作用，为这些患者提供更有效的治疗。© 2023。BioMed Central Ltd.，Springer Nature 旗下公司。

Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours.We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS.The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.© 2023. BioMed Central Ltd., part of Springer Nature.