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