Yang Liyu, Zhang Jing, Jiang Yiting, Zhang Jiayu, Wang Zhonghua, Wang Lihui, Fan Xinyu, Ba Gen
Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
Department of Bone & Soft tissue Oncology, People's Hospital of China Medical University (People's Hospital of Liaoning Province), Shenyang, Liaoning Province, China.
Chem Biol Interact. 2025 May 1;412:111451. doi: 10.1016/j.cbi.2025.111451. Epub 2025 Mar 6.
Osteosarcoma (OS) is a malignant bone tumor that occurs commonly in adolescents or children, previous studies have shown its complex epigenetic signature. Histone methyltransferases KMT2D loss-of-function mutation is common in various types of human cancer. Here we revealed that KMT2D loss promotes malignant phenotypes in osteosarcoma. Based on the result of epigenetic inhibitor library screening we discovered that KDM5B inhibitors selectively killed KMT2D-deficient cells. Also, the knockdown of KDM5B by shRNA could reduce cell proliferation, migration and induce apoptosis in KMT2D-KO cells, while no similar appearance was observed in wild-type cells. Furthermore, we testified the efficiency and safety of KDM5B inhibition in patient-derived xenografts (PDX) mouse models driven by KMT2D low-expressing patients. These results demonstrated KDM5B as a synthetic lethal factor of KMT2D-loss mutation. Our findings suggest a novel therapeutic strategy for treating KMT2D mutated osteosarcoma by targeting KDM5B.
骨肉瘤（OS）是一种常见于青少年或儿童的恶性骨肿瘤，先前的研究已经表明其具有复杂的表观遗传特征。组蛋白甲基转移酶KMT2D功能丧失突变在各种类型的人类癌症中很常见。在这里，我们揭示了KMT2D缺失会促进骨肉瘤的恶性表型。基于表观遗传抑制剂文库筛选结果，我们发现KDM5B抑制剂可选择性杀死KMT2D缺陷细胞。此外，通过shRNA敲低KDM5B可降低KMT2D基因敲除（KO）细胞的增殖、迁移并诱导其凋亡，而在野生型细胞中未观察到类似现象。此外，我们在由KMT2D低表达患者驱动的患者来源异种移植（PDX）小鼠模型中验证了抑制KDM5B的有效性和安全性。这些结果证明KDM5B是KMT2D缺失突变的合成致死因子。我们的研究结果表明，通过靶向KDM5B为治疗KMT2D突变的骨肉瘤提供了一种新的治疗策略。
