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.
Highlights
Histidine triad nucleotide-binding protein 1 (HINT1) is a member of the evolutionarily highly conserved HIT superfamily, which is divided into three branches, namely, the histidine triad nucleotide-binding protein (Hint) branch, the fragile histidine triad (Fhit) branch, and the galactose-1-phosphate uridyltransferase (GalT) branch
This study sought to identify potential acetyltransferases responsible for HINT1 acetylation. 293T cells were cotransfected with Flag-HINT1 and the major acetyltransferases p300, CBP, pCAF, GCN5, and Tip[60], which have been reported to have a critical role in acetylation of most cellular proteins[18] and were treated with nicotinamide (NAM), an inhibitor of the sirtuin family, and trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC) I/II
The function of HINT1 as a tumor suppressor is supported by observations that a deficiency of HINT1 in mice led to increased susceptibility to both spontaneous and carcinogen-induced tumor formation[4,5]
Summary
Histidine triad nucleotide-binding protein 1 (HINT1) is a member of the evolutionarily highly conserved HIT superfamily, which is divided into three branches, namely, the histidine triad nucleotide-binding protein (Hint) branch, the fragile histidine triad (Fhit) branch, and the galactose-1-phosphate uridyltransferase (GalT) branch. Many studies have suggested that HINT1 can serve as a novel tumor suppressor in various types of cancer, such as melanoma, gastric cancer, and colon cancer, and may have an important role in the treatment of neuropsychiatric diseases[2,3]. HINT1 overexpression reduces the growth rate of several cancer cells, such as melanoma, colon cancer, gastric cancer, and lung cancer, or induces apoptosis in SW480 and MCF7 cells[6,8,9,10], whereas Hint[1] deficiency enhances the growth and spontaneous immortalization of mouse embryonic fibroblasts[4], supporting the claim that HINT1 might act as a tumor suppressor in some types of cancer
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