# Peptide-based covalent inhibitor of tubulin detyrosination promotes mesenchymal-to-epithelial transition in lung cancer cells

## TL;DR

A new peptide-based inhibitor that targets tubulin detyrosination reverses cancer cell migration traits, offering a potential new approach for lung cancer treatment.

## Contribution

Development of a covalent VASH inhibitor that specifically targets tubulin detyrosination with low toxicity and high specificity.

## Key findings

- Inhibition of tubulin detyrosination increases E-cadherin and reduces mesenchymal markers like vimentin and N-cadherin.
- The inhibitor impairs collective cell migration and 3D spheroid formation in lung cancer cells.
- Tubulin detyrosination is shown to maintain mesenchymal properties in cancer cells.

## Abstract

The vast majority of cancers are derived from epithelial origin. The key mechanism which contributes to cancer progression and leads to metastasis is called epithelial-to-mesenchymal transition. It involves alteration in expression of important markers including downregulation of E-cadherin and upregulation of vimentin and N-cadherin. These changes result in more efficient cell migration and colony formation, a prerequisite for metastatic invasion. Here, using lung cancer cell lines as a model, we show that inhibition of a tubulin posttranslational modification called detyrosination reverts epithelial-to-mesenchymal transition. Importantly, reduced detyrosination increases the levels of E-cadherin with concomitant reduction of vimentin and N-cadherin, which strongly affects cell migration and colony formation. Taken together, our data establish detyrosination as a promising target for anticancer therapy.

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.