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1.
Exp Mol Med ; 52(11): 1831-1844, 2020 11.
Article in English | MEDLINE | ID: mdl-33219302

ABSTRACT

N-α-acetyltransferase 20 (Naa20), which is a catalytic subunit of the N-terminal acetyltransferase B (NatB) complex, has recently been reported to be implicated in hepatocellular carcinoma (HCC) progression and autophagy, but the underlying mechanism remains unclear. Here, we report that based on bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas data sets, Naa20 expression is much higher in HCC tumors than in normal tissues, promoting oncogenic properties in HCC cells. Mechanistically, Naa20 inhibits the activity of AMP-activated protein kinase (AMPK) to promote the mammalian target of rapamycin signaling pathway, which contributes to cell proliferation, as well as autophagy, through its N-terminal acetyltransferase (NAT) activity. We further show that liver kinase B1 (LKB1), a major regulator of AMPK activity, can be N-terminally acetylated by NatB in vitro, but also probably by NatB and/or other members of the NAT family in vivo, which may have a negative effect on AMPK activity through downregulation of LKB1 phosphorylation at S428. Indeed, p-LKB1 (S428) and p-AMPK levels are enhanced in Naa20-deficient cells, as well as in cells expressing the nonacetylated LKB1-MPE mutant; moreover, importantly, LKB1 deficiency reverses the molecular and cellular events driven by Naa20 knockdown. Taken together, our findings suggest that N-terminal acetylation of LKB1 by Naa20 may inhibit the LKB1-AMPK signaling pathway, which contributes to tumorigenesis and autophagy in HCC.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , N-Terminal Acetyltransferase B/metabolism , Protein Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , Acetylation , Autophagy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation , Chromatography, Liquid , Disease Susceptibility , Humans , Liver Neoplasms/pathology , Models, Biological , Signal Transduction , Tandem Mass Spectrometry
2.
Exp Mol Med ; 52(7): 1075-1089, 2020 07.
Article in English | MEDLINE | ID: mdl-32636443

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 Assays
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