Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes

// Laurence Froidevaux-Klipfel 1, * , Benjamin Targa 1 , Isabelle Cantaloube 1 , Hayat Ahmed-Zaid 1 , Christian Pous 1, 2 , Anita Baillet 1 1 INSERM, UMR-S-1193, Universite Paris-Saclay, Châtenay-Malabry, France 2 Laboratoire de Biochimie-Hormonologie, Hopital Antoine Beclere, AP-HP, Clamart, France * Present address: UMR 996, “Inflammation, chimiokines et immunopathologie,” INSERM, Universite Paris-Saclay, 92140 Clamart, France Correspondence to: Anita Baillet, e-mail: anita.baillet@u-psud.fr Keywords: septin, microtubule polyglutamylation, Taxol ® resistance, tyrosinated tubulin Received: June 29, 2015      Accepted: September 25, 2015      Published: October 07, 2015 ABSTRACT The mechanisms of cancer cell adaptation to the anti-microtubule agents of the taxane family are multifaceted and still poorly understood. Here, in a model of breast cancer cells which display amplified microtubule dynamics to resist Taxol ® , we provide evidence that septin filaments containing high levels of SEPT9_i1 bind to microtubules in a way that requires tubulin long chain polyglutamylation. Reciprocally, septin filaments provide a scaffold for elongating and trimming polyglutamylation enzymes to finely tune the glutamate side-chain length on microtubules to an optimal level. We also demonstrate that tubulin retyrosination and/or a high level of tyrosinated tubulin is crucial to allow the interplay between septins and polyglutamylation on microtubules and that together, these modifications result in an enhanced CLIP-170 and MCAK recruitment to microtubules. Finally, the inhibition of tubulin retyrosination, septins, tubulin long chain polyglutamylation or of both CLIP-170 and MCAK allows the restoration of cell sensitivity to taxanes, providing evidence for a new integrated mechanism of resistance.