Oncogene, 2018-05, Vol.37 (22), p.2967-2981
2018
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- Autor(en) / Beteiligte
- Titel
- Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression
- Ist Teil von
- Oncogene, 2018-05, Vol.37 (22), p.2967-2981
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/s41388-018-0172-9Titel-ID: cdi_proquest_miscellaneous_2012918797
- Format
- –
- Schlagworte
- 13/95, 14/19, 42, 42/89, 631/67/395, 631/80/458/1275, 82/1, Acetylation, Acetylation - drug effects, Acetyltransferase, Animals, Antidiabetics, Apoptosis, Autophagy, Cancer, Cell Biology, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Line, Tumor, Cell Movement - drug effects, Cell Proliferation - drug effects, Development and progression, Diabetes, Diabetes mellitus, Disease Progression, Down-Regulation, Drug therapy, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Genetic aspects, Health aspects, Human Genetics, Humans, Internal Medicine, Lysine, Lysine Acetyltransferase 5 - metabolism, Medicine, Medicine & Public Health, Melanoma, Melanoma - drug therapy, Melanoma - genetics, Melanoma - metabolism, Metastases, Metformin, Metformin - administration & dosage, Metformin - pharmacology, Mice, Mice, Inbred C57BL, Molecular modelling, Oncology, Patient outcomes, Patients, Phagocytosis, Phosphorylation, Proteasomes, Protein kinases, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Repressor Proteins - genetics, Repressor Proteins - metabolism, Smad3 protein, Smad3 Protein - genetics, Smad3 Protein - metabolism, Therapeutic applications, Transcription, Tumorigenesis, Tumors, Ubiquitin, Xenograft Model Antitumor Assays