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Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression

Oncogene volume 37, pages 2967–2981 (2018)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from National Key R&D Program of China (2017YFA0205400), from National Natural Science Foundation of China (81530093, 81773781 to Z.W.H.; 81101595, 81472717 to F.H.; 81400140 to K.L., 81503128 to X.X.L.), from Beijing Natural Science Foundation (7162133 to F.H.), and from CAMS Innovation Found for Medical Sciences (2016-I2M-1-007 to Z.W.H., F.H. and C.X.Z.; 2016-I2M-1-011 to K.L.; 2016-I2M-3-008 to B.C. and J.J.Y.; 2016-I2M-1-008 to X.X.L.).

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  1. These authors contributed equally: Ke Li and Ting-ting Zhang.

Authors and Affiliations

  1. Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Ke Li, Feng Wang, Bing Cui, Chen-xi Zhao, Jiao-jiao Yu, Xiao-xi Lv, Xiao-wei Zhang, Zhao-na Yang, Fang Hua & Zhuo-wei Hu

  2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Ke Li

  3. Shandong University, Weihai, 264209, China

    Ting-ting Zhang & Xia Li

  4. Institute of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Bo Huang

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Li, K., Zhang, Tt., Wang, F. et al. Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene 37, 2967–2981 (2018). https://doi.org/10.1038/s41388-018-0172-9

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