2. Academic Validation
  3. Identifying KDM5B as the synthetic lethal target of KMT2D-mutated osteosarcoma

Identifying KDM5B as the synthetic lethal target of KMT2D-mutated osteosarcoma

  • Chem Biol Interact. 2025 May 1:412:111451. doi: 10.1016/j.cbi.2025.111451.
Liyu Yang 1,  Jing Zhang 2,  Yiting Jiang 3,  Jiayu Zhang 4,  Zhonghua Wang 5,  Lihui Wang 6,  Xinyu Fan 7,  Gen Ba 8
Affiliations

Affiliations

  • 1 Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address: yanglycmu@126.com.
  • 2 Department of Bone & Soft tissue Oncology, People's Hospital of China Medical University (People's Hospital of Liaoning Province), Shenyang, Liaoning Province, China. Electronic address: 423720783@qq.com.
  • 3 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: 2890698632@qq.com.
  • 4 Women and Children's Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: 854747992@qq.com.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: 2233105737@qq.com.
  • 6 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, 117004, China. Electronic address: wlhcw@163.com.
  • 7 Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address: fanxy@sj-hospital.org.
  • 8 Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address: bagen1983@163.com.
PMID: 40054828 DOI: 10.1016/j.cbi.2025.111451
Abstract

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.

Keywords

Epigenetic regulation; KDM5B; KMT2D; Osteosarcoma; Synthetic lethal.

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