ATE1 activates ER-stress and UPR pathways in glioblastoma

Abstract

Post-translational modifications (PTM) have been recognized as a relevant regulation of key processes in cancer pathophysiology, such as cell migration, adhesion, and proliferation. N-terminal protein arginylation is an emerging PTM involved in tumor progression; however, the mechanisms by which this modification influences these events are poorly understood and vary according to cancer type. Glioblastoma (GBM) is an aggressive intra-axial brain tumor associated with poor prognosis, low survival, and high recurrence rate. We performed a study combining in silico, in vitro, and patients samples analysis to understand the impact of N-terminal protein arginylation in GBM, including overexpression and silencing of ATE1 in GBM-U87MG cell line with RNASeq analysis, immunofluorescence, and validation of the identified targets at the protein level by immunoblotting. The arginylation pattern differed in GBM compared with non-neoplastic brain tissues, and upregulation of ATE1 was associated with increased tumor cell proliferation. We identified a strong activation of the unfolded protein response (UPR) pathway associated with increased ATE1 level, inducing autophagy and not apoptosis. Protein arginylation in GBM proved to be an important mechanism for tumor growth, with the recycling of cell substrates by autophagy, providing fitness for tumor cells. The expressions of the main markers of UPR and autophagy pathways were validated in human GBM samples, reinforcing the role of ATE1 in the most aggressive brain tumor.