Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression
| العنوان: | Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression |
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| المؤلفون: | Bing Cui, Chen-xi Zhao, Bo Huang, Jiao-jiao Yu, Xiaoxi Lv, Xiaowei Zhang, Ke Li, Xia Li, Zhuo-Wei Hu, Tingting Zhang, Fang Hua, Zhao-na Yang, Feng Wang |
| المصدر: | Oncogene. 37:2967-2981 |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Down-Regulation, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Biology, Lysine Acetyltransferase 5, Metastasis, Mice, 03 medical and health sciences, Downregulation and upregulation, Cell Movement, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Smad3 Protein, KAT5, Melanoma, Molecular Biology, Cell Proliferation, Regulation of gene expression, Autophagy, Acetylation, medicine.disease, Xenograft Model Antitumor Assays, Metformin, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Repressor Proteins, 030104 developmental biology, TRIB3, Disease Progression, Cancer research, medicine.drug |
| الوصف: | Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression. Thus, TRIB3 is a potential therapeutic target for diverse cancers. In this study, we found that metformin attenuates melanoma growth and metastasis by reducing TRIB3 expression in non-diabetic C57BL/6 mice and diabetic KK-Ay mice; overexpression of TRIB3 protects metformin from the activation of autophagic flux, the clearance of accumulated tumour-promoting factors and the attenuation of tumour progression. We further elucidated that TRIB3 acts as an adaptor to recruit lysine acetyltransferase 5 (KAT5) to SMAD3 and induce a phosphorylation-dependent K333 acetylation of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation and decreases the KAT5/SMAD3 interaction, to attenuate the KAT5-mediated K333 acetylation of SMAD3, reduce the SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby antagonizes melanoma progression. Together, our study not only defines a molecular mechanism by which metformin protects against melanoma progression by disturbing the KAT5/TRIB3/SMAD3 positive feedback loop in diabetes and non-diabetes mice, but also suggests a candidate diverse utility of metformin in tumour prevention and therapy because of suppressing stress protein TRIB3 expression. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fdf3fc36f148445cdb5fc4df10ec00d2Test https://doi.org/10.1038/s41388-018-0172-9Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....fdf3fc36f148445cdb5fc4df10ec00d2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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