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αTAT1-induced tubulin acetylation promotes ameloblastoma migration and invasion.

ABSTRACT: Ameloblastoma (AB) is the most common benign epithelial odontogenic tumor occurring in the jawbone. AB is a slowly growing tumor but sometimes shows a locally invasive and an aggressive growth pattern with a marked bone resorption. In addition, the local recurrence and distant metastasis of AB also sometimes occurs, which resembles one of the typical malignant potentials. From these points of view, to understand better the mechanisms of AB cell migration or invasion is necessary for the better clinical therapy and improvements of the patients' quality of life. Microtubules in eukaryotic cells reveal the shape of hollow cylinders made up of polymerized alpha (α)- and beta (β)-tubulin dimers and form the cytoskeleton together with microfilaments and intermediate filaments. Microtubules play important roles in cell migration by undergoing assembly and disassembly with post-translational modifications. Stability of microtubules caused by their acetylation is involved in cell migration. In this study, we investigated the expression and distribution of acetylated α-tubulin and alpha-tubulin N-acetyltransferase 1 (αTAT1), an enzyme which acetylates Lys-40 in α-tubulin, in AB specimens, and analyzed how tubulin was acetylated by αTAT1 activation in a human AB cell line, AM-1. Finally, we clarified that TGF-β-activated kinase1 (TAK1) was phosphorylated by TGF-β stimulation, then, induced tubulin acetylation via αTAT1 activation, which subsequently activated the migration and invasion of AB cells.

SUBMITTER: Yoshimoto S

PROVIDER: S-EPMC8695380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Macroautophagy/autophagy, a fundamental process for degradation of macromolecules and organelles, occurs constitutively at a basal level and is upregulated in response to stress. Whether autophagy regulates protein acetylation and microtubule stability in vascular smooth muscle cells (VSMCs) migration, however, remains unknown. Here, we demonstrate that the histone acetyltransferase KAT2A/GCN5 (lysine acetyltransferase 2) binds directly to the autophagosome protein MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via a conserved LC3-interacting region (LIR) domain. This interaction is required for KAT2A sequestration in autophagosomes and degradation by lysosomal acid hydrolases. Suppression of autophagy results in KAT2A accumulation. KAT2A functions as an acetyltransferase to increase TUBA/α-tubulin acetylation, promote microtubule polymerization and stability, ultimately inhibiting directional cell migration. Our findings indicate that deacetylation of TUBA and perturbation of microtubule stability via selective autophagic degradation of KAT2A are essential for autophagy-promoting VSMC migration. Abbreviations: ACTB: actin beta; ATAT1: alpha tubulin acetyltransferase 1; ATG: autophagy-related; BECN1: beclin 1; CQ: chloroquine; FBS: fetal bovine serum; GST: glutathione S-transferase; H4K16ac: histone H4 lysine 16 acetylation; HASMCs: human aortic smooth muscle cells; HBSS: Hank's buffered salt solution; HDAC6: histone deacetylase 6; hMOF: human males absent on the first; IP: immunoprecipitation; KAT2A/GCN5: lysine acetyltransferase 2A; Lacta: lactacystin; LIR: LC3-interaction region; MAP1LC3: microtubule associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTOC: microtubule-organizing center; PE: phosphatidylethanolamine; PtdIns3K: class III phosphatidylinositol 3-kinase; RUNX2: runt-related transcription factor 2; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; VSMCs: vascular smooth muscle cells; WT: wild-type.

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αTAT1-induced tubulin acetylation promotes ameloblastoma migration and invasion.

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