Methyltransferase inhibitors interfere with Snail1 action on myofibroblast activity to prevent fibrosis and metastasis

Sala Romanyà, Laura

Methyltransferase inhibitors interfere with Snail1 action on myofibroblast activity to prevent fibrosis and metastasis

Document Type

Doctoral thesis
Published Version

Author

Sala Romanyà, Laura

Director

Baulida i Estadella, Josep

Publication Date

2018-06-20

Pages

161 p.

Citation

Sala Romanyà, L. Methyltransferase inhibitors interfere with Snail1 action on myofibroblast activity to prevent fibrosis and metastasis. Universitat Pompeu Fabra; 2018. handle: http://hdl.handle.net/10803/664117

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Snail1 is a transcription factor which activity is required for the fibroblasts-to-myofibroblast differentiation. In the first part of the thesis we characterize a protein complex involving Snail1, PRMT1 and PRMT4, two related members of the protein arginine methyltransferase (PRMT) family. Upon fibroblast activation with TGF-β, these enzymes interact with Snail1 and with the proximal Fibronectin promoter where Snail1 was described to bind. In fact, TGF-β induces Snail1-dependent arginine dimethylation on a set of proteins, including the H3 at the proximal Fibronectin promoter and several splicing regulators. We describe some TGF-β-induced alternative splicing events that are Snail1-dependent. In the second part, we use the methyltransferases inhibitors AMI-1 or Sinefungin to prevent myofibroblast activity in both cell culture and in vivo models. Of therapeutic interest for fibrosis and cancer, the inhibitors are effective in blocking the exacerbated activity of fibroblasts from idiopathic pulmonary fibrosis patients and Sinefungin efficiently interfered with the desmoplastic deposition in breast tumours and reduced the metastatic burden in mice. Our data reveal a new molecular pathway induced by Snail1 and point to methyltransferase inhibitors as potential reagents to prevent fibrosis and metastasis.
L’activitat del factor de transcripció Snail1 és necessària per l’activació de fibroblasts a miofibroblasts. En la primera part de la tesis caracteritzem un complex proteic que inclou Snail1, PRMT1 i PRMT4, dos membres d’una família de proteïnes que transfereixen grups metils a arginines (PRMTs). L’activació de fibroblasts amb TGF-β indueix la interacció d’aquests dos enzims amb Snail1 i amb el promotor proximal de Fibronectina on s’havia descrit que hi interaccionava Snail1. De fet, TGF-β indueix la dimetilació en arginines d’un conjunt de proteïnes en les que s’hi inclou la H3 del promotor proximal de Fibronectina i factors reguladors del processament (splicing) alternatiu de l’ARN. Hem descrit que TGF-β promou varis events de splicing alternatiu que depenen de Snail1. En la segona part, hem utilitzat els inhibidors de l’activitat de les metiltransferases, AMI-1 i Sinefungin per prevenir l’activitat dels miofibroblasts en cultius cel·lulars i en models in vivo. Els inhibidors bloquegen la hiperactivació de fibroblasts provinents de pacients amb fibrosis pulmonar idiopàtica i en ratolins la Sinefungin redueix la deposició d’estroma als tumours de mama i el número de metàstasi. El nostre treball revela una nova via molecular induïda per Snail1 i proposa els inhibidors de metiltransferases com a molècules amb potencial per a prevenir la fibrosis i les metàstasi.