SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

Michael M Ittmann,Edward T.H Yeh,Sue-Hwa Lin,Jinke Cheng,Tasneem Bawa-Khalfe

doi:10.1074/jbc.m110.134874

Abstract

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.

Highlights

Several large-scale gene expression studies report changes in the levels of SUMO E1, E2, and SENP1 in various cancers, suggesting an imbalance in the SUMO system (6 –9)
To promote the former, HIF1␣ increases the transcription of the vascular endothelial growth factor (VEGF), which in turn induces formation of the neovasculature or angiogenesis
We reported that SENP1 alters VEGF levels by directly regulating HIF1␣ stability during fetal development [12], but it is unknown whether SENP1 promotes angiogenesis via regulation of HIF1␣ in adult mice

Summary

Introduction

Several large-scale gene expression studies report changes in the levels of SUMO E1, E2, and SENP1 (sentrin/SUMO-specific protease 1) in various cancers, suggesting an imbalance in the SUMO system (6 –9). The number of nuclei that stained positive for PCNA was consistently greater in tissue samples from the 4-month-old C-line transgenic compared with the agematched wild-type mice (Fig. 3C), as assessment of three additional

Results

Conclusion