Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis

Abstract

Most prostate cancer cases remain indolent for long periods of time, but metastatic progression quickly worsens the prognosis and leads to mortality. However, little is known about what promotes the metastasis of prostate cancer and there is a lack of effective prognostic indicators, making it immensely difficult to manage options for treatment or surveillance. Arginyltransferase 1 (Ate1) is the enzyme mediating post-translational protein arginylation, which has recently been identified as a master regulator affecting many cancer-relevant pathways including stress response, cell cycle checkpoints, and cell migration/adhesion. However, the precise role of Ate1 in cancer remains unknown. In this study, we found the occurrence of metastasis of prostate cancer is inversely correlated with the levels of Ate1 protein and mRNA in the primary tumor. We also found that metastatic prostate cancer cell lines have a reduced level of Ate1 protein compared to non-metastatic cell lines, and that a depletion of Ate1 drives prostate cancer cells towards more aggressive pro-metastatic phenotypes without affecting proliferation rates. Furthermore, we demonstrated that a reduction of Ate1 can result from chronic stress, and that shRNA-reduced Ate1 increases cellular resistance to stress, and drives spontaneous and stress-induced genomic mutations. Finally, by using a prostate orthotropic xenograft mouse model, we found that a reduction of Ate1 was sufficient to enhance the metastatic phenotypes of prostate cancer cell line PC-3 in vivo. Our study revealed a novel role of Ate1 in suppressing prostate cancer metastasis, which has a profound significance for establishing metastatic indicators for prostate cancer, and for finding potential treatments to prevent its metastasis.

Multiple competing RNA structures dynamically control alternative splicing in human ATE1 gene

“…To test whether exons 7a and 7b are indeed spliced in a mutually exclusive manner, we analyzed a large compendium of RNA-seq experiments from the Genotype Tissue Expression (GTEx) project (34) ( Figure S1A). Consistent with previous reports (17), exons 7a and 7b have a broad range of inclusion levels across tissues (median 33% and 67%, respectively) with the most re-markable deviation in testis (median 60% and 39%, respectively). There was almost no evidence of simultaneous inclusion or simultaneous skip of both exons neither in normal tissues ( Figure S1A), nor in cancer samples from The Cancer Genome Atlas ( Figure S1B) (35).…”

“…Ate1 is essential in most eukaryotic systems and is implicated in regulation of many physiological pathways including proteolysis (3,4), response to stress and heat shock (5)(6)(7), embryogenesis (8)(9)(10), regenerative processes (11)(12)(13), and aging (14,15). Ate1 has recently been identified as a master regulator affecting disease-associated pathways (16)(17)(18), and its knockout results in embryonic lethality and severe developmental defects in mice (9,10,19,20).…”

Arginyltransferase knockdown attenuates cardiac hypertrophy and fibrosis through TAK1-JNK1/2 pathway

“…Having an insight into the mechanisms and potential targets implicit in cardiac hypertrophy will provide novel methodologies for the prevention or treatment of cardiovascular disease. Arginyltransferase (ATE1) is an evolutionary conserved enzyme and has a crucial role in multiple biological events [15][16][17] . The physiological importance of ATE1 in higher eukaryotes has been shown in previous studies where in case of Mus musculus, ATE1 deletion contributes to embryonic lethality due to abnormal cardiac morphogenesis and impaired angiogenesis 18 .…”

Long Non-coding RNA AGAP2-AS1 Silencing Inhibits PDLIM5 Expression Impeding Prostate Cancer Progression via Up-Regulation of MicroRNA-195-5p

“…As one of the most common cancers afflicting the male population, prostate cancer was previously reported to account for 1.2 million new cases diagnosed in 2018 (Bray et al, 2018). The greater majority of prostate cancers remain dormant or inactive for a considerable length of time, but metastatic progression is likely to rapidly lead to poor prognosis and death (Birnbaum et al, 2019). Prostate cancer treatment has witnessed substantial improvements over the past decade with novel therapeutics, improved functional imaging, and an improved application of existing therapies all reported to improve patient outcome (Teo et al, 2019).…”