Abstract
The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to β-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (No. 81974460; No. 81572649), Science and Technology Program of Guangzhou (No. 201803010023), Basic Research Project of Guangzhou Municipal Health Committee (No. 2060206), and Natural Science Foundation of Jiangxi Province (No. 20202BAB206077).
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WYF, ZL and YBW designed the research. JHL, HLY, STD, WFC, ZH, WWY, RTH, YHL, RTX, YYX, YS, LYW, PX, ZBZ, XL and YLD carried out the experiments and performed the data analysis. JHL wrote the manuscript. WYF revised the manuscript. All of the authors have read and approved the final manuscript.
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Liu, Jh., Yang, Hl., Deng, St. et al. The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma. Acta Pharmacol Sin 43, 2687–2695 (2022). https://doi.org/10.1038/s41401-022-00890-x
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DOI: https://doi.org/10.1038/s41401-022-00890-x
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