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Cancer Sci. 2019 Feb 4. doi: 10.1111/cas.13963. [Epub ahead of print]

Prothymosin-α Enhances PTEN Expression and Binds with TRIM21 to Regulate Keap1/Nrf2 Signaling in Human Bladder Cancer.

Author information

1
Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2
Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
3
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan.
4
Department of Biochemistry and Molecular biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5
Department of Urology, An-Nan Hospital, China Medical University, Tainan, Taiwan.

Abstract

Prothymosin-α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunologic functions. Previous studies demonstrated that aberrant location of PTMA expression exists in human bladder cancer, but the role of PTMA protein expression remains elusive. In this study, we created ectopic nuclear or cytoplasmic PTMA expression in human bladder cancer cells by infecting lentiviruses carrying wild-type, or deleted nuclear localization signal of PTMA gene. The in vivo tumorigenesis assay showed PTMA protein with deleted nuclear localization signal promotes J82 xenograft tumor growth in mice and shortens their survival than does the wild-type one. Chromatin immunoprecipitation showed wild-type PTMA protein binds to the PTEN promoter and enhances PTEN expression. Via immunoblot proteomics and in vivo ubiquitination studies, PTMA protein can bind with tripartite motif-containing protein 21 (TRIM21) and block its ubiquitination. Also, TRIM21 can downregulate both forms of PTMA protein. In human bladder tumors, loss of nuclear PTMA expression was an unfavorable prognostic indicator for shorter disease-free survival (hazard ratio, 1.54; p = 0.009). Our data support nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling. This article is protected by copyright. All rights reserved.

KEYWORDS:

Nfe2l2 protein; PTEN protein; TRIM21 protein; bladder cancer; prothymosin alpha

PMID:
30719818
DOI:
10.1111/cas.13963
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