2. Academic Validation
  3. Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification

Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification

  • J Orthop Translat. 2025 Oct 16:55:346-359. doi: 10.1016/j.jot.2025.09.007.
Binghui Yang 1 2,  Haoyu Wang 1 2,  Yining Tao 1 2,  Xiyu Yang 1 2,  Haoran Mu 1 2,  Liu Yang 1 2,  Yafei Jiang 1 2,  Zhuoying Wang 1 2,  Rui Zhang 3,  Zhengdong Cai 1 2,  Chunxi Yang 4,  Dongqing Zuo 1 2,  Yingqi Hua 1 2,  Wei Sun 1 2
Affiliations

Affiliations

  • 1 Department of Orthopaedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Bone Tumor Institution, Shanghai, China.
  • 3 Department of Orthopedics, Shanghai Sixth People's Hospital, Shanghai, China.
  • 4 Department of Orthopaedic Arthroplasty, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 41146859 DOI: 10.1016/j.jot.2025.09.007
Abstract

Background: Osteosarcoma (OS) is a highly aggressive primary bone tumor with poor outcomes, particularly in metastatic or recurrent cases. Methionine metabolism and histone methylation, such as H3K27me3, play crucial roles in OS progression.

Methods: We analyzed single-cell RNA Sequencing (scRNA-seq) data to identify histone methylation and related pathways associated with malignant proliferation OS cells. A high-throughput compound screen was performed to evaluate potential metabolic and epigenetic targets. In vitro and in vivo experiments were conducted to assess the therapeutic potential of MAT2A inhibition, methionine restriction, and EZH2 inhibition.

Results: MAT2A inhibition or methionine restriction reduced H3K27me3 levels, induced DNA damage, and suppressed OS cell growth. Combining MAT2A and EZH2 inhibitors demonstrated synergistic effects in reducing H3K27me3 levels, enhancing DNA damage, and inhibiting OS growth both in vitro and in vivo.

Conclusion: The combination of MAT2A and EZH2 inhibition significantly reduces intracellular H3K27me3 levels by depleting S-adenosylmethionine (SAM) and inhibiting synthetic enzyme activity, thereby inducing DNA damage in osteosarcoma (OS). Methionine-restricted diet combined with EZH2 inhibition effectively suppresses osteosarcoma growth in vivo.

The translational potential of this article: This study highlights the potential of integrating metabolic and epigenetic interventions in OS therapy. Our findings might present a promising therapeutic strategy for chemotherapy-resistance OS.

Keywords

DNA damage; EZH2; H3K27me3; MAT2A; Methionine metabolism; Osteosarcoma.

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