Arginyl‐tRNA‐protein transferase 1 (ATE1) promotes melanoma cell growth and migration

Abstract

Arginyl‐tRNA‐protein transferase 1 (ATE1) catalyses N‐terminal protein arginylation, a post‐translational modification implicated in cell migration, invasion and the cellular stress response. Herein, we report that ATE1 is overexpressed in NRAS‐mutant melanomas, while it is downregulated in BRAF‐mutant melanomas. ATE1 expression was higher in metastatic tumours, compared with primary tumours. Consistent with these findings, ATE1 depletion reduced melanoma cell viability, migration and colony formation. Reduced ATE1 expression also affected cell responses to mTOR and MEK inhibitors and to serum deprivation. Among putative ATE1 substrates is the tumour suppressor AXIN1, pointing to the possibility that ATE1 may fine‐tune AXIN1 function in melanoma. Our findings highlight an unexpected role for ATE1 in melanoma cell aggressiveness and suggest that ATE1 constitutes a potential new therapeutic target.

ATE1 activates ER-stress and UPR pathways in glioblastoma

“…Moreover, protein arginylation has been described as regulating cellular stress response 35,36,37 . Here, we demonstrated that upregulation of ATE1 was associated with UPR response that triggers cell survival in U87MG cells, as previously described in melanoma cells, where increased cell survival was related to ATE1 overexpression under stress condition triggered by serum deprivation 6 . In particular, we observed increased BIP arginylation in U87MG-ATE1+cells (Figure 4)…”

“…The preliminary in silico analysis of the TCGA-RNASeq dataset for GBM cases 30 and GTEx for normal brain samples 31 demonstrated a differential activation of arginylation between GBM and normal brain samples, and a poorer clinical outcome in GBM cases with increased ATE1 expression. Increased ATE1 level has already been correlated with increased cell migration and metastatic events in melanoma 6 . Although the mechanisms of tumorigenesis related to arginylation are not completely elucidated, arginylation has been linked to cell proliferation through AKT 32 .…”

“…Among the 42 upregulated genes in response to cellular stress, 28 genes were related to ER stress, being 16 genes related to unfolded protein, including transcription factors ( XBP1 , NFE2L2 ); ER chaperones ( CALR , CLGN , DNAJC3, PDI ); members of heat shock protein (Hsp) 70 family ( HYOU1 , BIP ); Hsp70 binding activity ( FICD ); ER transmembrane receptors related protein degradation ( AMFR ); ER sensor of unfolded proteins ( ERN1 , EIF2AK3 ); misfolded protein binding activity ( EDEM1 ); ER degradation of misfolded proteins ( DERL3 ); and ubiquitin protein ligase activity ( TMEM129 , TMBIM6 ). Genes coding for proteins related to autophagosome ( ULK , ATG5 , ATG13 ) and early endosomes ( PIKFYVE ) were also significantly upregulated in ATE1+ cells compared to VØ cells (logFC = 1.1, adjP < 4.38 x10 -6 ). Interestingly, TP53 was identified as a node interconnecting cellular response to stress, ER stress, autophagy, and negative regulation of cell death ( Figure 3D ).…”

“…However, the role of ATE1 in tumor progression is still poorly understood, and its effects differ depending on tumor type. In prostate 8 and liver cancer 9 , low ATE1 expression was correlated with aggressive tumor features, whereas in melanoma, high ATE1 expression was associated with increased migration, fitness in nutrient deprivation and metastasis, and also with lower survival rate 6 . There is no study about arginylation in brain tumors so far.…”

“…Protein arginylation is a post-translational modification (PTM) essential for mammalian embryogenesis and regulation of the cytoskeleton and also influences several cellular functions 4 , including cell survival under stressful conditions as endoplasmic reticulum (ER)-stress 5 , nutrient deprivation 6 , and heat stress 7 .…”