{"title":"DYRK2通过泛素化和Twist1降解控制GSTPI的表达，降低乳腺癌EMT引起的化疗耐药","authors":"Guofa Xu, MeiYu Zhou, Qian Li, YanYan Li, Chong Zhang, Zailiang Yang","doi":"10.1007/s10735-024-10300-7","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Breast cancer (BC) poses a significant global health challenge, with chemotherapy resistance, especially to docetaxel, remaining a major obstacle in effective treatment. The molecular mechanisms underlying this resistance are critical for developing targeted therapeutic strategies.</p><h3>Objective</h3><p>This study aims to explore the role of dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), a member of the DYRK family, in docetaxel resistance in breast cancer cells and investigate its impact on cellular responses, including drug sensitivity and migration. Additionally, potential interactions between DYRK2 and Twist1, associated with epithelial-mesenchymal transition (EMT) and drug resistance, are explored. Methods: Docetaxel-resistant breast cancer cells were induced, and the expression levels of DYRK2, Twist1, and related genes were evaluated using real-time PCR and Western blotting. Lentivirus-mediated DYRK2 overexpression was employed to assess its effect on drug sensitivity, migratory ability, and Twist1 expression. The relationship between DYRK2 and Twist1 was examined, focusing on Twist1 ubiquitination. The impact of Twist1 on chemotherapy resistance and its binding to the Glutathione S-transferase Pi 1 (GSTP1) promoter were also investigated.</p><h3>Results</h3><p>Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-π expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-π expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2’s ability to suppress chemoresistance in breast cancer cells.</p><h3>Conclusion</h3><p>DYRK2 plays a pivotal role in overcoming docetaxel resistance in breast cancer cells by suppressing Twist1 expression through ubiquitination, impacting downstream signaling and cellular responses. This study provides valuable insights for developing targeted therapies to improve breast cancer treatment outcomes.</p></div>","PeriodicalId":650,"journal":{"name":"Journal of Molecular Histology","volume":"56 1","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DYRK2 controls GSTPI expression through ubiquitination and degradation of Twist1 to reduce chemotherapy resistance caused by EMT in breast cancer\",\"authors\":\"Guofa Xu, MeiYu Zhou, Qian Li, YanYan Li, Chong Zhang, Zailiang Yang\",\"doi\":\"10.1007/s10735-024-10300-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Breast cancer (BC) poses a significant global health challenge, with chemotherapy resistance, especially to docetaxel, remaining a major obstacle in effective treatment. The molecular mechanisms underlying this resistance are critical for developing targeted therapeutic strategies.</p><h3>Objective</h3><p>This study aims to explore the role of dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), a member of the DYRK family, in docetaxel resistance in breast cancer cells and investigate its impact on cellular responses, including drug sensitivity and migration. Additionally, potential interactions between DYRK2 and Twist1, associated with epithelial-mesenchymal transition (EMT) and drug resistance, are explored. Methods: Docetaxel-resistant breast cancer cells were induced, and the expression levels of DYRK2, Twist1, and related genes were evaluated using real-time PCR and Western blotting. Lentivirus-mediated DYRK2 overexpression was employed to assess its effect on drug sensitivity, migratory ability, and Twist1 expression. The relationship between DYRK2 and Twist1 was examined, focusing on Twist1 ubiquitination. The impact of Twist1 on chemotherapy resistance and its binding to the Glutathione S-transferase Pi 1 (GSTP1) promoter were also investigated.</p><h3>Results</h3><p>Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-π expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-π expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2’s ability to suppress chemoresistance in breast cancer cells.</p><h3>Conclusion</h3><p>DYRK2 plays a pivotal role in overcoming docetaxel resistance in breast cancer cells by suppressing Twist1 expression through ubiquitination, impacting downstream signaling and cellular responses. This study provides valuable insights for developing targeted therapies to improve breast cancer treatment outcomes.</p></div>\",\"PeriodicalId\":650,\"journal\":{\"name\":\"Journal of Molecular Histology\",\"volume\":\"56 1\",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-12-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Histology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10735-024-10300-7\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Histology","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10735-024-10300-7","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
DYRK2 controls GSTPI expression through ubiquitination and degradation of Twist1 to reduce chemotherapy resistance caused by EMT in breast cancer
Background
Breast cancer (BC) poses a significant global health challenge, with chemotherapy resistance, especially to docetaxel, remaining a major obstacle in effective treatment. The molecular mechanisms underlying this resistance are critical for developing targeted therapeutic strategies.
Objective
This study aims to explore the role of dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), a member of the DYRK family, in docetaxel resistance in breast cancer cells and investigate its impact on cellular responses, including drug sensitivity and migration. Additionally, potential interactions between DYRK2 and Twist1, associated with epithelial-mesenchymal transition (EMT) and drug resistance, are explored. Methods: Docetaxel-resistant breast cancer cells were induced, and the expression levels of DYRK2, Twist1, and related genes were evaluated using real-time PCR and Western blotting. Lentivirus-mediated DYRK2 overexpression was employed to assess its effect on drug sensitivity, migratory ability, and Twist1 expression. The relationship between DYRK2 and Twist1 was examined, focusing on Twist1 ubiquitination. The impact of Twist1 on chemotherapy resistance and its binding to the Glutathione S-transferase Pi 1 (GSTP1) promoter were also investigated.
Results
Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-π expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-π expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2’s ability to suppress chemoresistance in breast cancer cells.
Conclusion
DYRK2 plays a pivotal role in overcoming docetaxel resistance in breast cancer cells by suppressing Twist1 expression through ubiquitination, impacting downstream signaling and cellular responses. This study provides valuable insights for developing targeted therapies to improve breast cancer treatment outcomes.
期刊介绍：
The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes.
Major research themes of particular interest include:
- Cell-Cell and Cell-Matrix Interactions;
- Connective Tissues;
- Development and Disease;
- Neuroscience.
Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance.
The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.
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