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

Sci Rep. 2022 Jul 16;12(1):12186. doi: 10.1038/s41598-022-16518-3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Neovascularization, Pathologic
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Plasminogen Activator Inhibitor 2
  • Tissue Plasminogen Activator
  • Urinary Bladder Neoplasms* / genetics
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Plasminogen Activator Inhibitor 1
  • Plasminogen Activator Inhibitor 2
  • SERPINE1 protein, human
  • Tissue Plasminogen Activator
  • Urokinase-Type Plasminogen Activator