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Updated: Jan 13, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification
Binghui Yang1,2, Haoyu Wang1,2, Yining Tao1,2
1Department of Orthopaedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Targeting methionine metabolism and histone methylation with MAT2A and EZH2 inhibitors shows promise for osteosarcoma (OS) treatment. Combined inhibition reduces tumor growth and DNA damage, offering a new strategy for aggressive bone cancer.
Area of Science:
- Oncology
- Epigenetics
- Metabolic Pathways
Background:
- Osteosarcoma (OS) is an aggressive bone cancer with poor prognosis, especially in advanced stages.
- Methionine metabolism and histone methylation (e.g., H3K27me3) are implicated in OS progression.
Purpose of the Study:
- Identify histone methylation pathways in OS using single-cell RNA sequencing.
- Evaluate therapeutic targets including methionine metabolism and epigenetic modifiers.
- Assess the efficacy of MAT2A inhibition, methionine restriction, and EZH2 inhibition in OS models.
Main Methods:
- Single-cell RNA sequencing analysis of OS cells.
- High-throughput compound screening for metabolic and epigenetic targets.
- In vitro and in vivo experiments evaluating MAT2A inhibition, methionine restriction, and EZH2 inhibition.
Main Results:
- MAT2A inhibition and methionine restriction decreased H3K27me3, induced DNA damage, and inhibited OS cell growth.
- Combined MAT2A and EZH2 inhibition synergistically reduced H3K27me3, enhanced DNA damage, and suppressed OS growth in vitro and in vivo.
Conclusions:
- Combined MAT2A and EZH2 inhibition depletes S-adenosylmethionine (SAM), reduces H3K27me3, and induces DNA damage in OS.
- Methionine restriction with EZH2 inhibition effectively suppressed in vivo osteosarcoma growth.
- This study suggests a promising therapeutic strategy combining metabolic and epigenetic interventions for chemo-resistant OS.
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