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Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage

Cancer Gene Therapy (2023)Cite this article

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Abstract

Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC.

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Fig. 1: Overexpression of EPS8 in cancer cell lines and clinical samples.
Fig. 2: Knockdown of EPS8 inhibits tumor cell growth, colony formation and migration.
Fig. 3: Chemosensitivity changes induced by stable EPS8 knockdown.
Fig. 4: Knockdown of EPS8 regulates downstream signals.
Fig. 5: Knockdown of EPS8 sensitized NSCLC cells to cisplatin by reducing DNA repair capacity.
Fig. 6: EPS8 knockdown sensitizes A549 to cisplatin in vivo.

Data availability

The datasets generated and/or analyzed during the current study are available in the [SangerBox] repository (http://www.sangerbox.com/).

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Acknowledgements

This work was supported by the [National Natural Science Foundation of China] under Grant [number 82270233, U2001224, 82100155]; the [China Postdoctoral Science Foundation] under Grant [number 2022M720060]; the [Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory] under Grant [number 2018GZR110105014]. The authors are grateful to Jingwen Du (Department of hematology, Zhujiang Hospital, Guangzhou, China) for her helpful technical advices throughout our research.

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Author notes

  1. These authors contributed equally: Yingqi Qiu, Binyan Xu, Jianhua Feng.

Authors and Affiliations

  1. Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 Gongye Dadao Zhong, Guangzhou, Guangdong, 510285, P. R. China

    Yingqi Qiu, Binyan Xu, Jianhua Feng, Chunsheng Wang, Yiran Chen, Yanjie He, Xiaoling Xie & Yuhua Li

  2. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, 510005, P. R. China

    Yuhua Li

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Contributions

All authors have made substantial contributions to this article. Under the supervision of Y.L. and X.X designed the study and experiments. X.X., Y.Q., B.X., J.F., and C.W. performed the experiments, collected the data, conducted the analysis, and wrote the manuscript. J.F, C.W., Y.C., and Y.H. revised the manuscript. All authors have read and approved this work.

Corresponding authors

Correspondence to Xiaoling Xie or Yuhua Li.

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Ethical approval

The study was conducted in accordance with the ARRIVE guidelines. The design and final reports of this study complied with the Helsinki Declaration and were approved by the Ethical Review Board of Zhujiang Hospital of Southern Medical University (Guangzhou, China). Informed consent was obtained from all patients with clinical samples. The ethical review board of Zhujiang Hospital approved the use of human tissues. The in vivo experiments were carried out in accordance with the Southern Medical University’s Policy on Care and Use of Laboratory Animals and ARRIVE guidelines. The study was reviewed and approved by the Ethical Review Board of Zhujiang Hospital.

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The authors declare no competing interests.

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Qiu, Y., Xu, B., Feng, J. et al. Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage. Cancer Gene Ther (2023). https://doi.org/10.1038/s41417-023-00606-1

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