Genetic disruption of tubulin acetyltransferase, αTAT1, inhibits proliferation and invasion of colon cancer cells through decreases in Wnt1/β-catenin signaling

Microtubules are required for diverse cellular processes, and abnormal regulation of microtubule dynamics is closely associated with severe diseases including malignant tumors. In this study, we report that a-tubulin N-acetyltransferase (alpha TAT1), a regulator of a-tubulin acetylation, is required for colon cancer proliferation and invasion via regulation of Wntl and its downstream genes expression. Public transcriptome analysis showed that expression of ATATI is specifically upregulated in colon cancer tissue. A knockout (KO) of ATATI in the HCT116 colon cancer cell line, using the CRISPRICas9 system showed profound inhibition of proliferative and invasive activities of these cancer cells. Overexpression of alpha TAT1 or the acetyl-mimic K40Q alpha-tubulin mutant in aTATl KO cells restored the invasiveness, indicating that microtubule acetylation induced by aTAT1 is critical for HCI116 cell invasion. Analysis of colon cancer-related gene expression in alpha TAT1 KO cells revealed that the loss of alpha TAT1 decreased the expression of WNT1. Mechanistically, abrogation of tubulin acetylation by alpha TATl knockout inhibited localization of beta-catenin to the plasma membrane and nucleus, thereby resulting in the downregulation of Wntl and of its downstream genes including CCND1, MMP-2, and MMP-9. These results suggest that aTAT1-mediated Wntl expression via microtubule acetylation is important for colon cancer progression. (C) 2016 Elsevier Inc. All rights reserved.