MP-08.22

Lekas, A.; Lazaris, Andreas C.; Nakopoulou, Lydia; Chrisofos, Michael; Lappas, Dimitrios; Papathomas, Thomas; Fokitis, I.; Koritsiadis, S.; Deliveliotis, Ch.

doi:10.1016/j.urology.2006.08.329

Cited by 1 publication

(1 citation statement)

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“…In this study, nuclear expression of HIF1␣ was greater in the samples from patients with higher Gleason grades (Fig. 6, D-F, black arrows); this observation is in accord with previous reports (23,24). The increase in the nuclear expression of HIF1␣ accompanied the elevation of SENP1 levels in each PCa grade (Fig.…”

Section: Senp1 Transgenic Mice Enhance Angiogenesis Via Stabilizationsupporting

confidence: 92%

SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

Bawa-Khalfe

Cheng

Lin

et al. 2010

Journal of Biological Chemistry

101

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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 1␣ (HIF1␣) expression. Mechanistic studies in a mouse model indicate that androgen-driven expression of murine SENP1 leads to HIF1␣ 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 HIF1␣-dependent angiogenesis and enhanced cell proliferation.SUMO (small ubiquitin-like modifier) modification of protein substrates is a dynamic process that modulates the target protein's expression, function, and/or subcellular location (1, 2). SUMOylation is regulated by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by a family of sentrin/SUMO-specific proteases (3-5). These enzymes are critical for maintaining a balance between the level of SUMOylated and unmodified cellular substrates and hence play an important role in mediating normal cellular physiology.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). SENP1 mRNA levels are elevated in thyroid oncocytic adenocarcinoma (6) and human prostate cancer (PCa) 3 (10). In addition, using in situ hybridization, we recently found greater SENP1 mRNA levels in precancerous prostatic intraepithelial neoplasia (PIN) compared with adjacent normal prostate epithelia (10). Transformation of the normal prostate epithelia to carcinoma is preceded by the development of this well characterized PIN state (11). The presence of elevated SENP1 levels in this precursor state posed the question as to whether SENP1 induction is not associated merely with the carcinoma but instead could directly contribute to prostate carcinogenesis.Recently, we demonstrated that SENP1 enhances the stability of hypoxia-inducing factor 1␣ (HIF1␣) and, consequently, HIF1␣-mediated transcription; in the absence of SENP1, HIF1␣ is actively SUMOylated and subsequently degraded under hypoxic conditions (12). In prostate carcinogenesis, hypoxic tissue environments emerge due to rapidly proliferating cancer cells, and HIF1␣ is post...

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Section: Senp1 Transgenic Mice Enhance Angiogenesis Via Stabilizationsupporting

confidence: 92%