Abstract
Cisplatin is the effective chemotherapeutic drug in colon cancer treatment, but its therapeutic efficacy is limited by intrinsic or acquired drug resistance and detrimental side effects. Therefore, improving the effect of cisplatin chemotherapy remains a great challenge. The previous study identified that USP39 was relevant to cisplatin resistance of lung cancer. However, the function and mechanisms of USP39 regulating the chemosensitivity of cisplatin in colorectal cancer remain unclear. In this study, we reveal that USP39 is associated with colon cancer cells sensitivity to cisplatin. Depletion of USP39 enhances the cisplatin-induced apoptosis in HCT116 cells. Conversely, overexpression of USP39 attenuates apoptosis in RKO cells. Furthermore, we demonstrate that USP39 depletion promotes apoptosis induced by cisplatin, which is related with the induction of oxidative stress and DNA damage response. Further studies show that USP39 regulates cisplatin-induced apoptosis dependent on p53. The underlying mechanism is demonstrated by knocking down USP39, that results in p53 upregulation, associated with its prolonged half-life. Collectively, our findings reveal that USP39 might be a negative factor of the p53 mediated cisplatin sensitivity of colon cancer, and suggest USP39 as a potential molecular target for cisplatin chemotherapy of colon cancer.
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Most of data and materials generated or analyzed during this study are included in this published. Other data are available from the corresponding authors on reasonable request.
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Acknowledgements
We thank Prof. Han You for HCT116p53null cell line, and we also would like to acknowledge the editors and reviewers for their helpful suggestions on this manuscript.
Funding
This work is supported by the grants from the National Natural Science Foundation of China (81872045), and the Special Fund for Public Welfare Research Institutes of Fujian Province (2020R11010032-3).
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Jiahui Yuan and Gang Song designed and conceived the experiments; Jiahui Yuan, Xiaomei Li, and Yuqi Zhang performed the experiments and collected and analyzed data; Weiwei Wang, Weipeng Cheng, and Yongbin Lei collected data, and provided support for flow cytometry; Jiahui Yuan wrote the paper; Jiahui Yuan and Gang Song were responsible for the revision of manuscript. All authors read and approved the final manuscript.
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All animal research protocols were approved by the Institutional Animal Care and Use Committee of Xiamen University (IACUC No. XMULAC20180056).
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Highlights
1. USP39 attenuates the antitumor activity of cisplatin on colon cancer cells.
2. USP39 depletion enhances cisplatin-induced apoptosis via the induction of oxidative stress and DNA damage response.
3. USP39 regulates cisplatin-induced apoptosis dependent on p53.
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Yuan, J., Li, X., Zhang, Y. et al. USP39 attenuates the antitumor activity of cisplatin on colon cancer cells dependent on p53. Cell Biol Toxicol 39, 1995–2010 (2023). https://doi.org/10.1007/s10565-021-09683-0
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DOI: https://doi.org/10.1007/s10565-021-09683-0