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

Oncogenevolume 37pages29672981 (2018) | Download Citation

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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Author notes

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

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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The authors declare that they have no conflict of interest.

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Correspondence to Fang Hua or Zhuo-wei Hu.

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https://doi.org/10.1038/s41388-018-0172-9