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PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores

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Abstract

Cuproptosis is a new Cu-dependent programmed cell death manner that has shown regulatory functions in many tumor types, however, its mechanism in bladder cancer remains unclear. Here, we reveal that Phosphodiesterase 3B (PDE3B), a cuproptosis-associated gene, could reduce the invasion and migration of bladder cancer. PDE3B is downregulated in bladder cancer tissues, which is correlated with better prognosis. Conversely, overexpression of PDE3B in bladder cancer cell could significantly resist invasion and migration, which is consistent with the TCGA database results. Future study demonstrate the anti-cancer effect of PDE3B is mediated by Keratin 6B (KRT6B) which leads to the keratinization. Therefore, PDE3B can reduce KRT6B expression and inhibit the invasion and migration of bladder cancer. Meanwhile, increased expression of PDE3B was able to enhance the sensitivity of Cuproptosis drug thiram. This study show that PDE3B/KRT6B is a potential cancer therapeutic target and PDE3B activation is able to increase the sensitivity of bladder cancer cells to copper ionophores.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PDE3B:

Phosphodiesterase 3B

KRT6B:

Keratin 6B

TCA:

Tricarboxylic Acid Cycle

CRGs:

Cuproptosis-Related Genes

BLCA:

Bladder Urothelial Carcinoma

OS:

Overall Survival

GSEA:

Gene Set Enrichment Analysis

KEGG:

Kyoto Encyclopedia of Genes and Genomes

PPI:

Protein Protein Interaction Network

GO:

Gene Ontology

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Acknowledgements

We thank Prof. Yang Fu and Dr. Jiehan Li from Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University for providing virus packaging plasmids.

Funding

This work was supported by the National Natural Science Foundation of China (grant number: 82172564) and The Joint project of Medical science and technology of Henan Province (grant number: LHGJ20220341).

Author information

Author notes

  1. Yuankang Feng, Zhenlin Huang and Liang Song contributed equally.

Authors and Affiliations

  1. Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Yuankang Feng, Zhenlin Huang, Liang Song, Ningyang Li, Xiang Li, Ruoyang Liu, Fubo Lu, Xu Han, Yafei Ding, Yinghui Ding, Jun Wang, Jinjian Yang & Zhankui Jia

  2. Department of Otology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Yinghui Ding

  3. Department of Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Huihui Shi

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  1. Yuankang Feng
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Contributions

Z.J., J.Y. conceived the study. Y.F., Z.H., L.S. and J.W. designed the experiments. X.L., H.S., R.L., N.L., F.L., X.H., Y.D. and Y.D. conducted experiments and data collection and analysis, and/or generated cell lines. Y.F., Z.H., L.S., Z.J. wrote the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Jinjian Yang or Zhankui Jia.

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Institutional review board statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2022-KY-1384).

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Feng, Y., Huang, Z., Song, L. et al. PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4911–4925 (2024). https://doi.org/10.1007/s00210-023-02928-1

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