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FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells

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Abstract

As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228/Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228/Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROS/NF-κB/IκB-α and Wnt/β-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228/Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.

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Data availability

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

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Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (81872394), the Natural Science Foundation of Liaoning Province of China (2020-MS-187), and Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University for the generous financial support (LR2020080).

Funding

This study was supported by the National Natural Science Foundation of China, 81872394 and Natural Science Foundation of Liaoning Province, 2020-MS-187 to Daiying Zuo.

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Authors and Affiliations

  1. Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China

    Yuying Yang, Yang Li, Qian Yang, Zi Liu, Xing Chang, Huan Yang, Jingang Liu, Zengqiang Li & Daiying Zuo

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  1. Yuying Yang
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  2. Yang Li
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  3. Qian Yang
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  4. Zi Liu
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  6. Huan Yang
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  7. Jingang Liu
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  8. Zengqiang Li
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  9. Daiying Zuo
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Contributions

YY: Methodology, Investigation, Formal analysis, Writing-Original Draft. YL, QY and ZL: Investigation, Methodology, Validation. Xing Chang: Methodology, Resources. HY and JL: Investigation, Validation. ZL: Software, Resources. DZ: Conceptualization, Project administration, Funding acquisition, Writing-Review and Editing.

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Correspondence to Daiying Zuo.

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Yang, Y., Li, Y., Yang, Q. et al. FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells. Med Oncol 40, 64 (2023). https://doi.org/10.1007/s12032-022-01934-2

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