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

https://www.ncbi.nlm.nih.gov/pubmed/34681055

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.