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

Abstract

Experimental & molecular medicine: tumor suppression: minor modifications aid cancer control A crucial modification to the tumor-suppressing gene HINT1 helps slow the spread of colon cancer and melanoma according to researchers in South Korea. HINT1 is known to bind to and inhibit several tumor-promoting transcription factors, but it is unclear how this process is regulated. Hyun-Seok Kim at Ewha Womans University in Seoul and co-workers focused on SIRT1, an enzyme that deacetylates, i.e., removes acetyl groups from, various important proteins. They found that the deacetylation of HINT1 by SIRT1 promotes the capacity of HINT1 to bind to transcription factors, thereby enhancing its tumor-suppressing function. Mutant colon cancer and melanoma cell lines with completely deacetylated HINT1 showed significantly reduced growth. The researchers suggest that acetylation and other reversible modifications of HINT1, such as phosphorylation, could be useful in clinical treatments. 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 beta-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 beta-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.