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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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.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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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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