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.
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