Prothymosin-α enhances phosphatase and tensin homolog expression and binds with tripartite motif-containing protein 21 to regulate Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 signaling in human bladder cancer.

Abstract

Prothymosin-α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunological 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 the 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 more so than the wild type. Chromatin immunoprecipitation showed that wild-type PTMA protein binds to the PTEN promoter and enhances phosphatase and tensin homolog (PTEN) expression. Through 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 that nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.

• Authors: Yuh-Shyan Tsai, Yeong-Chin Jou, Hsin-Tzu Tsai, Ai-Li Shiau, Chao-Liang Wu, Tzong-Shin Tzai
• Journal: Cancer science (Cancer Sci) Vol. 110 Issue 4 Pg. 1208-1219 (Apr 2019) ISSN: 1349-7006 [Electronic] England
• PMID: 30719818 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Biomarkers
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Protein Precursors
• Ribonucleoproteins
• SS-A antigen
• prothymosin alpha
• Thymosin
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Biomarkers
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Mice
• NF-E2-Related Factor 2 (metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Prognosis
• Promoter Regions, Genetic
• Protein Precursors (genetics, metabolism)
• Ribonucleoproteins (metabolism)
• Signal Transduction
• Thymosin (analogs & derivatives, genetics, metabolism)
• Ubiquitination
• Urinary Bladder Neoplasms (genetics, metabolism, mortality, pathology)