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Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells

Oncogene volume 36, pages 4732–4738 (2017)Cite this article

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Abstract

Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger Ap4A to HINT1. Ap4A is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the Ap4A-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-Ap4A-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.

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Acknowledgements

We thank Prof Norman Grover from the Hebrew University for conducting the statistical analysis. Patient-derived cutaneous metastatic melanoma cells (line TC-2514) were kindly provided by Dr John Wunderlich (Surgery Branch National Cancer Institute). This work was supported in part by grants from the National Institute of Health GM100136 and American Asthma Foundation AAF15-0080 to MG, and National Research Foundation of Singapore (Hebrew University of Jerusalem—Campus for Research Excellence and Technological Enterprise) and Israel Science Foundation to ER and the Israel Cancer Association, Boca Grove Fellowship Fund to ER.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

    A Motzik, E Amir, T Erlich & E Razin

  2. State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    J Wang

  3. Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea

    B-G Kim

  4. Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, South Korea

    J M Han

  5. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, South Korea

    J M Han

  6. College of Pharmacy, Yonsei University, Seoul, South Korea

    J H Kim

  7. Oncology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    H Nechushtan

  8. Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA

    M Guo

  9. Department of Nuclear Medicine, Kaplan Medical Center, Rehovot, Israel

    S Tshori

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  1. A Motzik
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Correspondence to E Razin.

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Motzik, A., Amir, E., Erlich, T. et al. Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells. Oncogene 36, 4732–4738 (2017). https://doi.org/10.1038/onc.2017.81

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