SENP1 induces prostatic intraepithelial neoplasia through multiple mechanisms

J Biol Chem. 2010 Aug 13;285(33):25859-66. doi: 10.1074/jbc.M110.134874. Epub 2010 Jun 15.


SUMOylation has been shown to modulate DNA replication/repair, cell cycle progression, signal transduction, and the hypoxic response. SUMO (small ubiquitin-like modifier)-specific proteases regulate SUMOylation, but how changes in the expression of these proteases contribute to physiological and/or pathophysiological events remains undefined. Here, we show that SENP1 (sentrin/SUMO-specific protease 1) is highly expressed in human prostate cancer specimens and correlates with hypoxia-inducing factor 1alpha (HIF1alpha) expression. Mechanistic studies in a mouse model indicate that androgen-driven expression of murine SENP1 leads to HIF1alpha stabilization, enhanced vascular endothelial growth factor production, and angiogenesis. Further pathological assessment of the mouse indicates that SENP1 overexpression induces transformation of the normal prostate gland and gradually facilitates the onset of high-grade prostatic intraepithelial neoplasia. Consistent with cell culture studies, SENP1 enhances prostate epithelial cell proliferation via modulating the androgen receptor and cyclin D(1). These results demonstrate that deSUMOylation plays a critical role in prostate pathogenesis through induction of HIF1alpha-dependent angiogenesis and enhanced cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Proliferation
  • Cysteine Endopeptidases
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Endopeptidases / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / physiopathology
  • Prostatic Intraepithelial Neoplasia / etiology*
  • Prostatic Intraepithelial Neoplasia / genetics
  • Prostatic Neoplasms / etiology*
  • Prostatic Neoplasms / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Endopeptidases
  • Cysteine Endopeptidases
  • Senp1 protein, mouse