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FOXO3 Inhibits the Cisplatin Resistance and Progression of Melanoma Cells by Promoting CDKN1C Transcription

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Abstract

Background

Forkhead box O3 (FOXO3) and cyclin dependent kinase inhibitor 1 C Gene (CDKN1C) have been shown to be involved in the melanoma process, but their roles in the cisplatin (DDP) resistance of melanoma remain unclear.

Methods

The mRNA levels of CDKN1C and FOXO3 were measured using quantitative real-time PCR. The protein levels of CDKN1C, FOXO3 and mitochondrial oxidative phosphorylation (mtOXPHOS)-related markers were determinant by western blot analysis. The DDP resistance, proliferation, and apoptosis of melanoma cells were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Glucose consumption, lactate production and ATP level were detected to assess glycolysis. The regulation of FOXO3 on CDKN1C was confirmed by ChIP assay and dual-luciferase reporter assay. In vivo experiments were performed to evaluate the effect of FOXO3 on DDP sensitivity in melanoma tumor tissues.

Results

CDKN1C and FOXO3 were downregulated in chemoresistant melanoma tissues, and their low expression levels were related to the poor prognosis of melanoma patients. Overexpression of CDKN1C and FOXO3 repressed DDP resistance, proliferation, and glycolysis, while promoted apoptosis and mtOXPHOS in DDP-resistant melanoma cells. Further analysis suggested that FOXO3 could bind to CDKN1C promoter region to enhance its transcription. Besides, CDKN1C knockdown reversed the regulation of FOXO3 on melanoma cell DDP resistance and progression. Moreover, FOXO3 overexpression enhanced the DDP sensitivity of melanoma tumor tissues in vivo.

Conclusion

FOXO3 promoted the transcription of CDKN1C, thereby inhibiting the DDP resistance and progression of melanoma cells.

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Data Availability

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Acknowledgements

None.

Funding

This work was supported by 2021 Xiangyang City Research and Development Project (Medical and Health Technology Program) (2021YL08).

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Author notes

  1. Chao Yang and Zeqiang Yan contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei, 441021, China

    Chao Yang, Zhihua Sun & Fen Hu

  2. Department of Gastroenterology, Affiliated Hospital of Hubei, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei, 441021, China

    Zeqiang Yan

  3. Department of Dermatology, Affiliated Hospital of Hubei, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei, 441021, China

    Wei Xu

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  1. Chao Yang
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Contributions

Chao Yang and Zeqiang Yan designed and performed the research; Zhihua Sun, Fen Hu, Wei Xu analyzed the data; Chao Yang and Zeqiang Yan wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wei Xu.

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Yang, C., Yan, Z., Sun, Z. et al. FOXO3 Inhibits the Cisplatin Resistance and Progression of Melanoma Cells by Promoting CDKN1C Transcription. Appl Biochem Biotechnol (2024). https://doi.org/10.1007/s12010-024-04909-3

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