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Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway

Cancer Gene Therapy (2024)Cite this article

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Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy.

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Fig. 1: HTS indicates that romidepsin inhibits ESCC cell proliferation in both 2D and 3D culture systems.
Fig. 2: The anti-ESCC activity of romidepsin in vitro.
Fig. 3: The anti-ESCC activity of romidepsin in CDX models.
Fig. 4: Romidepsin enhances DDIT4 expression through histone hyperacetylation at its promoter region.
Fig. 5: DDIT4-mTORC1 pathway mediates the inhibitory effect of romidepsin on the biological behaviors of ESCC cells.
Fig. 6: The efficacy and toxicity of romidepsin in ESCC PDX models.
Fig. 7: Romidepsin inhibits ESCC by activating DDIT4-mTORC1 pathway.

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Correspondence and requests for materials should be addressed to LX-W (lxwu@cqmu.edu.cn).

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Acknowledgements

This work was supported by the Natural Science Foundation of China (No. 82073938, 82274023, 82373135), Youth Innovation in Future Medicine, Chongqing Medical University (No. W0093), and the Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJQN202200432).

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  1. These authors contributed equally: Wei-Feng Xia, Xiao-Li Zheng, Wen-Yi Liu.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Wei-Feng Xia & Qing-Chen Wu

  2. Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China

    Xiao-Li Zheng, Wen-Yi Liu, Yu-Tang Huang, Chun-Jie Wen & Lan-Xiang Wu

  3. Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, China

    Hong-Hao Zhou

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Contributions

WFX: Methodology, Formal analysis, Investigation, Writing – original draft. XLZ: Methodology, Formal analysis, Investigation. WYL: Methodology, Resources. YTH: Formal analysis, Investigation. CJW: Investigation. HHZ: Data interpretation. QCW: Project administration, Supervision. LXW: Writing-review & editing, Supervision, Project administration, Funding acquisition.

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Correspondence to Qing-Chen Wu or Lan-Xiang Wu.

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Xia, WF., Zheng, XL., Liu, WY. et al. Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00760-0

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