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EZH2 inhibitor Tazemetostat synergizes with JQ-1 in esophageal cancer by inhibiting c-Myc signaling pathway

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Abstract

EZH2, a highly conserved histone methyltransferase, plays an essential role in tumorigenesis and development. The inhibitor of EZH2 tazemetostat has been approved to treat metastatic or locally advanced epithelioid sarcoma and recurrent or refractory follicular lymphoma. However, the effect of tazemetostat alone or in combination with other drugs in esophageal cancer has not been reported. In this study, we found that EZH2 was highly expressed in esophageal cancer at both mRNA and protein levels through transcriptomic and proteomic analyses. Furthermore, the results of CCK8, colony formation, cell cycle and cell apoptosis assays revealed that tazemetostat exerted an antitumour effect on esophageal cancer cells. Mechanistically, RNA-sequencing analysis of the tazemetostat-treated cells and vehicle-treated ones suggested that tazemetostat mainly inhibited the c-Myc signaling pathway and its targets, which was validated by western blotting. JQ-1, an inhibitor of bromodomain 4, was proven to attenuate c-Myc signaling in tumors. Thus, a therapeutic strategy based on tazemetostat in combination with JQ-1 is promising. The results demonstrated that tazemetostat and JQ-1 had a synergistic effect in vitro and in vivo for esophageal cancer.

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Data Availability

All the data supporting the findings of this study are available upon reasonable request. Raw data for RNA-seq were deposited in the SRA database under accession number SUB12215728.

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Funding

This work was supported by start-up funds for the introduction of talents from the First Affiliated Hospital of Xiamen University (3502Z20214ZD3010), Health Youth Scientific Research Project of Fujian Province (2020QNB057; 2021QNB015), and the Natural Science Foundation of Fujian Province, China (2020J011238; 2021J05291; 2022J05304).

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Author notes

  1. Nan Ding and Abin You contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, School of Medicine, the First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, China

    Nan Ding, Abin You, Senxia Zhao, Hu Yang & Feng Ye

  2. The Third Clinical Medical College, Fujian Medical University, FuZhou, China

    Nan Ding, Abin You, Chunping Lai & Feng Ye

Authors
  1. Nan Ding
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  2. Abin You
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  3. Senxia Zhao
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  4. Hu Yang
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  5. Chunping Lai
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  6. Feng Ye
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Contributions

Feng Ye and Nan Ding generated the ideas for the study and wrote the manuscript. Nan Ding and Abin You conducted the experiments of the clinical specimens and performed the molecular biological experiments with the assistance of Senxia Zhao. Hu Yang and Chunping Lai did the animal experiment. All authors participated in editing the paper. All authors approved the final manuscript.

Corresponding author

Correspondence to Feng Ye.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Xiamen University.

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Informed consent was obtained from all individual participants included in the study.

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The authors have no relevant financial or non-financial interests to disclose.

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Ding, N., You, A., Zhao, S. et al. EZH2 inhibitor Tazemetostat synergizes with JQ-1 in esophageal cancer by inhibiting c-Myc signaling pathway. Med Oncol 40, 281 (2023). https://doi.org/10.1007/s12032-023-02147-x

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