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Ubiquitin carboxyl-terminal hydrolase isozyme L1/UCHL1 suppresses epithelial–mesenchymal transition and is under-expressed in cadmium-transformed human bronchial epithelial cells

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Abstract

Cadmium (Cd), a highly toxic heavy metal, is widespreadly distributed in the environment. Chronic exposure to Cd is associated with the development of several diseases including cancers. Over the decade, many researches have been carried on various models to examine the acute effects of Cd; yet, limited knowledge is known about the long-term Cd exposure, especially in the human lung cells. Previously, we showed that chronic Cd-exposed human bronchial epithelial BEAS-2B cells exhibited transformed cell properties, such as anchorage-independent growth, augmented cell migration, and epithelial–mesenchymal transition (EMT). To study these Cd-transformed cells more comprehensively, here, we further characterized their subproteomes. Overall, a total of 63 differentially expressed proteins between Cd-transformed and passage-matched control cells among the five subcellular fractions (cytoplasmic, membrane, nuclear-soluble, chromatin-bound, and cytoskeletal) were identified by mass spectrometric analysis and database searching. Interestingly, we found that the thiol protease ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) is one of the severely downregulated proteins in the Cd-transformed cells. Notably, the EMT phenotype of Cd-transformed cells can be suppressed by forced ectopic expression of UCHL1, suggesting UCHL1 as a crucial modulator in the maintenance of the proper differentiation status in lung epithelial cells. Since EMT is considered as a critical step during malignant cell transformation, finding novel cellular targets that can antagonize this transition may lead to more efficient strategies to inhibit cancer development. Our data report for the first time that UCHL1 may play a function in the suppression of EMT in Cd-transformed human lung epithelial cells, indicating that UCHL1 might be a new therapeutic target for chronic Cd-induced carcinogenesis.

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Acknowledgments

We would like to thank members of the Lau And Xu laboratory for critical reading of this manuscript and also Prof. dr. Irene Heijink, University Medical Center Groningen, the Netherlands for providing the PBECs.

Funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 31771582 and 31170785); the Guangdong Natural Science Foundation of China (No. 2017A030313131); the “Thousand, Hundred, and Ten” project of the Department of Education of Guangdong Province of China, the Basic and Applied Research Major Projects of Guangdong Province of China (2017KZDXM035 and 2018KZDXM036); the “Yang Fan” Project of Guangdong Province of China (Andy T. Y. Lau-2016; Yan-Ming Xu-2015); and the Abel Tasman Talent Program at the University Medical Center Groningen, the Netherlands.

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Author notes

  1. Dan-Dan Wu and Yan-Ming Xu contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, People’s Republic of China

    Dan-Dan Wu, Yan-Ming Xu, De-Ju Chen, Zhan-Ling Liang, Xu-Li Chen & Andy T. Y. Lau

  2. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713, GZ, Groningen, The Netherlands

    Dan-Dan Wu, Machteld N. Hylkema & Marianne G. Rots

  3. GRIAC Research Institute, University of Groningen, University Medical Center Groningen, 9713, GZ, Groningen, The Netherlands

    Dan-Dan Wu & Machteld N. Hylkema

  4. Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China

    Sheng-Qing Li

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  1. Dan-Dan Wu
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Correspondence to Andy T. Y. Lau.

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Graphical headlights

• Subcellular proteomeanalysis was conducted to identify global changes in the protein expressionprofiles of chronic cadmium-exposed human bronchial epithelial BEAS-2B cells

• UCHL1 is under-expressed incadmium-transformed human BEAS-2B cells

• We found that loss of UCHL1plays a function on EMT in these cells

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Wu, DD., Xu, YM., Chen, DJ. et al. Ubiquitin carboxyl-terminal hydrolase isozyme L1/UCHL1 suppresses epithelial–mesenchymal transition and is under-expressed in cadmium-transformed human bronchial epithelial cells. Cell Biol Toxicol 37, 497–513 (2021). https://doi.org/10.1007/s10565-020-09560-2

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  • DOI: https://doi.org/10.1007/s10565-020-09560-2

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