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Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin
Chao He1, Jian Sun2, Chao Liu3
1Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Background:
In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS.
Results:
First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and KDM6B that were upregulated after cisplatin treatment. Consistent with the clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, we evaluated the effects of H3K27me3 alteration on OS chemosensitivity. In vitro inhibition of the histone methyltransferase EZH2 in OS cells decreased H3K27me3 levels and led to cisplatin resistance. Conversely, inhibition of the demethylases KDM6A and KDM6B increased H3K27me3 levels in OS and reversed cisplatin resistance in vitro and in vivo. Mechanistically, with the help of RNA sequencing (RNAseq), we found that PRKCA and MCL1 directly participated in the process by altering H3K27me3 on their gene loci, ultimately inactivating RAF/ERK/MAPK cascades and decreasing phosphorylation of BCL2.
Conclusions:
Our study reveals a new epigenetic mechanism of OS resistance and indicates that elevated H3K27me3 levels can sensitize OS to cisplatin, suggesting a promising new strategy for the treatment of OS.
Insights
Chemotherapy resistance in osteosarcoma (OS) is a major challenge. This study reveals that increasing histone H3K27me3 levels can resensitize OS to cisplatin, offering a new therapeutic strategy.
Area of Science:
- Epigenetics
- Cancer Biology
- Pharmacology
Background:
- Chemotherapy resistance in osteosarcoma (OS) significantly contributes to patient mortality.
- The underlying mechanisms of drug resistance in OS are not fully understood, hindering effective treatment.
- This study investigates the role of dynamic histone modifications in cisplatin resistance in OS.
Purpose of the Study:
- To explore the relationship between histone changes and cisplatin efficacy in osteosarcoma.
- To identify specific histone modifications and related enzymes involved in chemoresistance.
- To evaluate the potential of targeting epigenetic modifications to overcome cisplatin resistance in OS.
Main Methods:
- Analysis of histone demethylases KDM6A and KDM6B in relation to H3K27me3 levels after cisplatin treatment.
- In vitro and in vivo experiments involving inhibition of EZH2 (methyltransferase) and KDM6A/KDM6B (demethylases) in OS cells.
- RNA sequencing (RNAseq) to elucidate downstream molecular mechanisms, including PRKCA, MCL1, and the RAF/ERK/MAPK pathway.
Main Results:
- Histone demethylases KDM6A and KDM6B were upregulated post-cisplatin treatment, correlating with decreased H3K27me3 levels in resistant OS specimens.
- Inhibition of EZH2 reduced H3K27me3 and induced cisplatin resistance, while inhibiting KDM6A/KDM6B increased H3K27me3 and reversed resistance.
- RNAseq identified PRKCA and MCL1 as key players, with altered H3K27me3 on their loci affecting RAF/ERK/MAPK signaling and BCL2 phosphorylation.
Conclusions:
- A novel epigenetic mechanism underlying OS cisplatin resistance involving H3K27me3 dynamics was uncovered.
- Elevated H3K27me3 levels demonstrate the capacity to sensitize osteosarcoma to cisplatin.
- Targeting H3K27me3 levels presents a promising therapeutic strategy for overcoming chemotherapy resistance in OS.
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