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Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers

Oncogene volume 35, pages 4058–4068 (2016)Cite this article

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Abstract

Arginylation is an emerging post-translational modification mediated by arginyltransferase (ATE1) that is essential for mammalian embryogenesis and regulation of the cytoskeleton. Here, we discovered that Ate1-knockout (KO) embryonic fibroblasts exhibit tumorigenic properties, including abnormally rapid contact-independent growth, reduced ability to form cell–cell contacts and chromosomal aberrations. Ate1-KO fibroblasts can form large colonies in Matrigel and exhibit invasive behavior, unlike wild-type fibroblasts. Furthermore, Ate1-KO cells form tumors in subcutaneous xenograft assays in immunocompromised mice. Abnormal growth in these cells can be partially rescued by reintroduction of stably expressed specific Ate1 isoforms, which also reduce the ability of these cells to form tumors. Tumor array studies and bioinformatics analysis show that Ate1 is downregulated in several types of human cancer samples at the protein level, and that its transcription level inversely correlates with metastatic progression and patient survival. We conclude that Ate1-KO results in carcinogenic transformation of cultured fibroblasts, suggesting that in addition to its previously known activities Ate1 gene is essential for tumor suppression and also likely participates in suppression of metastatic growth.

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Acknowledgements

This work was supported by NIH grants GM104003 and GM117984 and the Pilot Grant from the Mari Lowe Center for Comparative Oncology to AK. BG was supported by the OTKA K108655 grant. MS was supported by NIH grant GM109091. FZ, MDB and A Kumar were partly supported by a Developmental Grant from Sylvester Comprehensive Cancer Center.

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Author notes

  1. R Rai and F Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    R Rai, F Zhang, K Colavita, N A Leu, S Kurosaka & A Kashina

  2. Department of Molecular & Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    F Zhang, A Kumar & M D Birnbaum

  3. MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary

    B Győrffy

  4. Second Department of Pediatrics, Semmelweis University, Budapest, Hungary

    B Győrffy

  5. Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania,, Philadelphia,, PA, USA

    D W Dong

  6. University of South Carolina, Columbia, SC, USA

    M Shtutman

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  1. R Rai
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  2. F Zhang
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  3. K Colavita
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  4. N A Leu
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  11. A Kashina
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Correspondence to A Kashina.

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Supplementary Information accompanies this paper on the Oncogene website

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Rai, R., Zhang, F., Colavita, K. et al. Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers. Oncogene 35, 4058–4068 (2016). https://doi.org/10.1038/onc.2015.473

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  • DOI: https://doi.org/10.1038/onc.2015.473

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