Deacetylation by SIRT1 promotes the tumor-suppressive activity of HINT1 by enhancing its binding capacity for β-catenin or MITF in colon cancer and melanoma cells

Exp Mol Med. 2020 Jul;52(7):1075-1089. doi: 10.1038/s12276-020-0465-2. Epub 2020 Jul 7.

Abstract

Histidine triad nucleotide-binding protein 1 (HINT1), which belongs to the evolutionarily conserved HIT superfamily, has been shown to possess a tumor-suppressive function by binding to and inhibiting several oncogenic transcription factors, such as β-catenin and microphthalmia transcription factor (MITF), in various types of cancer cells. However, the regulatory mechanism that mediates the binding capacity of HINT1 for partner transcription factors remains elusive. Here, we report that HINT1 is acetylated by CBP at K21 and K30 and deacetylated by SIRT1. Deacetylation of HINT1 by SIRT1 increases the capacity of HINT1 to bind to β-catenin or MITF. As a result, the tumor-suppressive function of HINT1 is increased. In support of this, the deacetylation mimetic HINT1 mutant HINT1 2KR was found to significantly reduce cellular proliferation in colon cancer and melanoma cells and tumorigenesis in xenograft assays. Thus, this study reveals an acetylation-dependent regulatory mechanism that governs the tumor-suppressive function of HINT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism*
  • HEK293 Cells
  • Humans
  • Lysine / metabolism
  • Male
  • Melanoma / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptide Fragments / metabolism
  • Protein Binding
  • Sialoglycoproteins / metabolism
  • Sirtuin 1 / metabolism*
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*

Substances

  • HINT1 protein, human
  • Microphthalmia-Associated Transcription Factor
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Sialoglycoproteins
  • beta Catenin
  • bone sialoprotein (35-62), human
  • Sirtuin 1
  • Lysine