PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity

• Published in: Scientific reports 2022-07, Vol.12 (1), p.12186-12186, Article 12186
• Main Authors: Furuya, Hideki, Sasaki, Yuka, Chen, Runpu, Peres, Rafael, Hokutan, Kanani, Murakami, Kaoru, Kim, Nari, Chan, Owen T. M., Pagano, Ian, Dyrskjøt, Lars, Jensen, Jørgen B., Malmstrom, Per-Uno, Segersten, Ulrika, Sun, Yijun, Arab, Abolfazl, Goodarzi, Hani, Goodison, Steve, Rosser, Charles J.
• Format: Article
• Language: English
• Subjects: 631/67/395; 631/67/589/1336; 631/67/68; Angiogenesis; Bladder cancer; Cancer; Cell survival; Chromatin; Cytoplasm; Fibrinolysis; Gene expression; Gene regulation; Humanities and Social Sciences; Humans; Immunoprecipitation; Localization; Malignancy; Mass spectrometry; Mass spectroscopy; multidisciplinary; Neovascularization, Pathologic; Nucleotide sequence; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen Activator Inhibitor 2; Plasminogen activator inhibitors; Regulatory sequences; Science; Science (multidisciplinary); t-Plasminogen activator; Tissue Plasminogen Activator; Tumor cell lines; Tumors; U-Plasminogen activator; Urinary Bladder Neoplasms - genetics; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-16518-3

The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.