Alpha-tubulin acetyltransferase/MEC-17 regulates cancer cell migration and invasion through epithelial\u2013mesenchymal transition suppression and cell polarity disruption

Cheng-Che Lee,Jang-Yang Chang,Chi-Yen Chang,Chi-Min Lin,Yun-Ching Cheng

doi:10.1038/s41598-018-35392-6

Abstract

MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. Alteration of α-tubulin acetylation may be involved in morphology regulation, cell migration, and tumour metastasis. However, MEC-17’s role in cell physiology and its effect on epithelial–mesenchymal transition (EMT) and cell polarity remain elusive. In the present study, we characterized the overexpressed or downregulated cell models through gene targeting as MEC-17 gain- or loss-of-function. Overexpression of MEC-17 enhanced the cell spreading area, suppressed pseudopods formation in a three-dimensional (3D) culture system, and inhibited cancer cell migratory and invasive ability and tumour metastasis by orthotopic lung cancer animal model. Furthermore, morphological change and migration inhibition of cancer cells were accompanied by EMT repression, Golgi reorientation, and polarity disruption caused by alteration of cdc42 activity via a decrease in Rho-GAP, ARHGAP21. By contrast, a reduction in endogenous MEC-17 accelerated the pseudopods formation and EMT, and facilitated cell migration and invasion. These results demonstrated the crucial role of MEC-17 in the modulation of intrinsic cell morphogenesis, migration, and invasive function through regulation of EMT and cell polarity.

Highlights

Epithelial–mesenchymal transition (EMT) is a crucial process that causes epithelial cells to acquire mesenchymal-like morphology and properties, thereby increasing their migration ability[1,2]
Because an increase in α-tubulin acetylation can increase the cell adhesion area[27], we examined whether MEC-17 overexpression affects cell morphology
To examine whether the MEC-17-induced lower cell motility was due to inhibition of cell proliferation, we evaluated the natural cell growth assay of A549 parental, vector control and MEC-17-overexpressed cells to determine the doubling time (DT)

Summary

Introduction

Epithelial–mesenchymal transition (EMT) is a crucial process that causes epithelial cells to acquire mesenchymal-like morphology and properties, thereby increasing their migration ability[1,2]. How tubulin acetylation induces cell death and subsequently suppresses tumour progression remains poorly understood. MEC-17 is an α-tubulin acetyltransferase for tubulin PTM, its effects on cell physiology as well as the molecular mechanism underlying its role in cancer cell morphology and motility through regulation of EMT and cell polarity remain poorly understood. Expressing MEC-17 cells, which showed asthenic tumour metastatic ability, exhibited suppression of EMT, redistribution of cell polarization, higher cdc[42] activity, and downregulation of Rho-GAP, ARHGAP21. Inhibition of cdc[42] activity restored MEC-17-induced EMT repression, cell polarization disorientation, and migration attenuation. Despite the crucial role of MEC-17 in α-tubulin acetylation for MTs stability and cytoskeletal organization, MEC-17 could be a novel regulator of EMT process through polarity modification and small GTPase activity

Methods

Results

Conclusion