Peptide-based covalent inhibitor of tubulin detyrosination promotes mesenchymal-to-epithelial transition in lung cancer cells
Abstract
Detyrosination is a reversible posttranslational modification specific to α-tubulin, which has been implicated in cancer progression and invasiveness by promoting epithelial-to-mesenchymal transition. The members of the vasohibin family, VASH1 and VASH2, were previously identified as the first class of enzymes involved in catalyzing this modification. Here, we report the development of a covalent VASH inhibitor, which is characterized by high specificity and low toxicity. By combining the use of a new compound with molecular approaches in lung cancer cell lines, we find that tubulin detyrosination plays an important role in the maintenance of mesenchymal properties. We show that in the absence of VASH activity, collective cell migration and 3D spheroid formation are severely compromised. Moreover, we demonstrate that the observed phenotypes are caused by the accumulation of the important epithelial marker E-cadherin with simultaneous reduction in mesenchymal markers N-cadherin and vimentin. Taken together, our study establishes tubulin detyrosination as a promising target for the future development of anticancer treatment.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (10)
Hathaichanok Impheng
Department of Physiology, Faculty of Medical Science, Naresuan University
Ghislain Gillard
Tubulin Code team, Institute of Human Genetics, CNRS, Université Montpellier
Nuttanid Numnoi
Department of Physiology, Faculty of Medical Science, Naresuan University
Anthony Feral
IBMM (Institut des Biomolécules Max Mousseron), Amino Acids, Peptides and Proteins department, Université de Montpellier, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier
Matthieu Simon
IBMM (Institut des Biomolécules Max Mousseron), Amino Acids, Peptides and Proteins department, Université de Montpellier, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier
Maxime Louet
IBMM (Institut des Biomolécules Max Mousseron), Amino Acids, Peptides and Proteins department, Université de Montpellier, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier
Muriel Amblard
IBMM (Institut des Biomolécules Max Mousseron), Amino Acids, Peptides and Proteins department, Université de Montpellier, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier
François Juge
Tubulin Code Team, IGH (Institute of Human Genetics) UMR 9002, Genetics, Cell Biology and Development department, Univ Montpellier, CNRS
Lubomir Vezenkov
IBMM (Institut des Biomolécules Max Mousseron), Amino Acids, Peptides and Proteins department, Université de Montpellier, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier
Krzysztof Rogowski
Tubulin Code team, Institute of Human Genetics, CNRS, Université Montpellier