Jawhar Wajih, Danieau Geoffroy, Annett Alva, Ishii Takeaki, Bajic Andrea, Castillo-Orozco Ana, Krug Brian, Faucher-Jabado Yara, Seyedmoomenkashi Justin, Saquib Mostafa, Aghababazadeh Masoumeh, Khatami Marjan, Tawil Nadim, Faury Damien, Jung Sungmi, Aoude Ahmed, Turcotte Robert E, Ellezam Benjamin, Sontag Thomas, Langlois Sylvie, Sinnett Daniel, Bailey Swneke D, Zhang Lingxin, Soglio Dorothée Dal, Kleinman Claudia L, Jabado Nada, Garzia Livia
Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Cancer Research Program, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
Nat Commun. 2025 Jul 22;16(1):6752. doi: 10.1038/s41467-025-61558-8.
Osteosarcomas (OS) are aggressive bone tumors known for their extensive structural variations and rare recurrent oncogenic driver mutations. In this study, we identify ectopic expression of the oncohistone-mimic EZHIP in 20% of patients across two independent OS cohorts. We demonstrate that reduced deposition of the repressive H3K27me3 mark correlates with poor histological response to neoadjuvant therapy, serving as a predictor of patient outcomes. Through gain- and loss-of-function experiments, we provide functional evidence of the oncogenic activity of EZHIP in enhancing the aggressive characteristics of OS both in vitro and in vivo. EZHIP-induced epigenetic reprogramming reactivates developmental pathways and impedes the differentiation of mesenchymal progenitors, pushing them towards smooth muscle lineage commitment at the cost of other fates. Targeting residual H3K27me3 with EZH2 inhibitors may offer therapeutic benefit in EZHIP-expressing OS. Our findings highlight EZHIP expression as a prevalent driver in OS, offering insights into its pathogenic mechanisms and potential therapeutic strategies for this debilitating cancer.
骨肉瘤（OS）是一种侵袭性骨肿瘤，以其广泛的结构变异和罕见的复发性致癌驱动基因突变而闻名。在本研究中，我们在两个独立的骨肉瘤队列中发现，20%的患者存在癌组蛋白模拟物EZHIP的异位表达。我们证明，抑制性H3K27me3标记的沉积减少与新辅助治疗的组织学反应不佳相关，可作为患者预后的预测指标。通过功能获得和功能丧失实验，我们提供了EZHIP致癌活性的功能证据，表明其在体外和体内均可增强骨肉瘤的侵袭性特征。EZHIP诱导的表观遗传重编程重新激活了发育途径，并阻碍了间充质祖细胞的分化，促使它们以牺牲其他命运为代价向平滑肌谱系定向分化。使用EZH2抑制剂靶向残留的H3K27me3可能对表达EZHIP的骨肉瘤具有治疗益处。我们的研究结果突出了EZHIP表达是骨肉瘤中一种普遍的驱动因素，为其致病机制和针对这种使人衰弱的癌症的潜在治疗策略提供了见解。
