GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback.
Fiche publication
Date publication
septembre 2021
Journal
Biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BAGUET Aurélie, Pr GUITTAUT Michaël, Dr FRAICHARD Annick, Dr HERVOUET Eric, Dr DESPOUY Gilles, Pr FEUGEAS Jean-Paul
Tous les auteurs :
Jacquet M, Hervouet E, Baudu T, Herfs M, Parratte C, Feugeas JP, Perez V, Reynders C, Ancion M, Vigneron M, Baguet A, Guittaut M, Fraichard A, Despouy G
Lien Pubmed
Résumé
The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial-mesenchymal transition (EMT) during cancer's etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.
Mots clés
ATG8, EMT, GABARAPL1, SMAD, autophagy, cancer
Référence
Biology (Basel). 2021 Sep 24;10(10):