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

A Motzik1, E Amir1, T Erlich1

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

Oncogene
|April 11, 2017
PubMed

Insights

Post-translational modifications of histidine triad nucleotide-binding protein 1 (HINT1) in melanoma cells enhance the activity of the microphthalmia transcription factor (MITF) oncogene. This manipulation affects the Lysyl-tRNA synthetase-Ap4A-HINT1-MITF signaling pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Microphthalmia transcription factor (MITF) is a key regulator in various cell types.
  • Histidine triad nucleotide-binding protein 1 (HINT1) inhibits MITF activity by direct binding.
  • The interaction between HINT1 and MITF is modulated by the second messenger Ap4A.

Purpose of the Study:

  • To investigate the role of HINT1 post-translational modifications in regulating MITF activity.
  • To explore the impact of these modifications on melanoma oncogenic potential.
  • To elucidate the LysRS-Ap4A-HINT1-MITF signaling pathway in melanoma.

Main Methods:

  • Analysis of HINT1 acetylation and phosphorylation in activated mast cells.
  • Site-directed mutagenesis to assess the functional impact of HINT1 modifications.
  • Evaluation of MITF transcriptional and oncogenic activity in human melanoma cell lines.

Main Results:

  • HINT1 undergoes K21 acetylation and Y109 phosphorylation in activated mast cells.
  • These modifications promote HINT1 dissociation from MITF, triggered by Ap4A.
  • Mutational analysis confirmed that HINT1 modifications enhance MITF activity in melanoma cells.

Conclusions:

  • Post-translational modifications of HINT1 are crucial regulators of MITF activity.
  • Targeting the LysRS-Ap4A-HINT1-MITF pathway through HINT1 modifications offers a potential strategy for melanoma treatment.
  • This study highlights the significance of HINT1 modifications in melanoma oncogenesis.

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