The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma
The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma
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DOI：
10.1038/s41401-022-00890-x
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发表时间：
2022-03-16
影响因子：
8.2
通讯作者：
Fang, Wei-yi
中科院分区：
文献类型：
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作者：
Liu, Jia-hao;Yang, Hui-ling;Fang, Wei-yi
据报道，小分子化合物cinobufotalin （CB）是一种潜在的抗肿瘤药物，可增加鼻咽癌患者对顺铂（DDP）的敏感性。在本研究中，我们首次发现，在肺腺癌（LUAD）中，CB降低了DDP的耐药性、迁移和侵袭。机制研究表明，CB通过抑制PI3K/AKT信号通路下调ENKUR负转录因子c-Jun来诱导ENKUR表达。此外，ENKUR通过与β -catenin结合来降低c-Jun的表达，从而抑制MYH9的转录，从而发挥肿瘤抑制作用。有趣的是，MYH9是ENKUR的结合蛋白。ENKUR的Enkurin结构域与MYH9结合，MYH9的Myosin_tail与ENKUR结合。MYH9的下调减少了去泛素酶USP7的募集，导致c-Myc泛素化和降解增加，c-Myc核易位减少，上皮-间质转化（EMT）信号失活，从而减弱DDP抗性。我们的数据表明，CB是一种很有前景的抗肿瘤药物，可能是LUAD患者的候选化疗药物。
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 beta-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.