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 ß-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 ß-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.
Subject(s)
Colonic Neoplasms/metabolism , Melanoma/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Nerve Tissue Proteins/metabolism , Sirtuin 1/metabolism , beta Catenin/metabolism , Acetylation , Animals , Cell Line, Tumor , HEK293 Cells , Humans , Lysine/metabolism , Male , Mice, Inbred BALB C , Mice, Nude , Mutation/genetics , Peptide Fragments/metabolism , Protein Binding , Sialoglycoproteins/metabolism , Transcription, Genetic , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: This randomized, controlled study was designed to compare the effects of recruitment maneuvers (RMs) with a 15 cmH2O positive end-expiratory pressure (PEEP) on the systemic oxygenation and lung compliance of patients with healthy lungs following robot-assisted laparoscopic prostatectomy (RALP). METHODS: Sixty patients undergoing a RALP with an intraoperative 15 cmH2O PEEP were randomly allocated to an RM or a Control group. The patients in the RM group received a single RM through the application of a continuous positive airway pressure of 40 cmH2O for 40 s 15 min after being placed in the Trendelenburg position. The arterial oxygen tension (PaO2, primary endpoint) and the pulmonary dynamic and static compliances (secondary endpoints) were measured 10 min after the anesthetic induction (T1), 10 min after establishment of the pneumoperitoneum (T2), 10 min after establishment of the Trendelenburg position (T3), 10 min after the RM (T4), 60 min after the RM (T5), and 10 min after deflation of the pneumoperitoneum in the supine position (T6). RESULTS: The intergroup comparisons of the PaO2 showed significantly higher values in the RM group than in the Control group at T4 and T5 (193 ± 35 mmHg vs. 219 ± 33 mmHg, P = 0.015, 188 ± 41 mmHg vs. 214 ± 42 mmHg, P = 0.005, respectively). However, the PaO2 at T6 was similar in the two groups (211 ± 39 mmHg vs. 224 ± 41 mmHg, P = 0.442). Moreover, there were no statistical differences between the groups in the dynamic and static compliances of the lungs at any time point. CONCLUSIONS: The arterial oxygenation of the patients with a healthy lung function who had undergone a RALP with intraoperative 15 cmH2O PEEP was improved by a single RM. However, this benefit did not last long, and it did not lead to an amelioration of the lung mechanics.
