ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion

Abstract

Invasive tumor cells use proteases to degrade and migrate through the stromal environment consisting of a 3D network of extracellular matrix macromolecules. In particular, MT1-MMP, a membrane-anchored metalloproteinase, is critical during cancer cell invasion. MT1-MMP is stored in endosomal compartments and then delivered to invadopodia, the specialized plasma membrane domains of invasive cancer cells endowed with extracellular matrix-degradation capacity. In macrophages, traffic of MT1-MMP vesicles to invadopodia-related podosomes requires microtubules. We previously found that in breast tumor MDA-MB-231 cells an increase of microtubule and cortactin acetylation upon inhibition of HDAC6 correlates with a decrease of matrix degradation and invasion in three-dimensional collagen I gel. Here, we investigated the role of the recently identified α-tubulin N-acetyltransferase 1 ATAT1 in invasive MDA-MB-231 cells. We found that the dynamics and distribution of MT1-MMP-positive endosomes require regulation of acetylation levels. We observed that ATAT1 tubulin acetyltransferase binds and regulates cortactin acetylation levels. In addition, ATAT1 colocalizes with cortactin at the adherent surface of the cells and it is required for 2D migration and invasive migration of MDA-MB-231 cells in collagen matrix. All together, our data indicate that a balance of acetylation and deaceylation by ATAT1/HDAC6 enzymes with opposite activities regulates the migratory and invasive capacities of breast tumor cells.