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Downregulation of zinc finger protein 132 in prostate cancer is associated with aberrant promoter hypermethylation and poor prognosis


Abildgaard, M O; Borre, M; Mortensen, M M; Ulhøi, B P; Tørring, N; Wild, P; Kristensen, H; Mansilla, F; Ottosen, P D; Dyrskjøt, L; Orntoft, T F; Sørensen, K D (2011). Downregulation of zinc finger protein 132 in prostate cancer is associated with aberrant promoter hypermethylation and poor prognosis. International Journal of Cancer:1-11.

Abstract

This study investigates the expression and biomarker potential of zinc finger protein 132 (ZNF132) in prostate cancer (PC) by transcriptional profiling and immunohistochemical analysis of tissue microarrays, including tumor specimens from 615 radical prostatectomy (RP) patients and 199 conservatively treated patients. Primary clinical endpoints were time to PSA recurrence and cancer-specific death, respectively. Compared to normal prostate epithelial cells from men without PC, ZNF132 transcript levels were significantly reduced in PC cells from patients with localized PC and further downregulated in metastatic PC. Likewise, ZNF132 protein expression was significantly lower in primary tumors from patients with metastatic compared to localized PC and further reduced in castrate-refractory PC, indicating that ZNF132 downregulation correlates with disease progression. Reduced ZNF132 immunoreactivity was significantly associated with high Gleason score and advanced T stage in both PC patient cohorts. By univariate analysis, no/weak ZNF132 staining was a significant adverse predictor of PSA recurrence after RP (p = 0.024) and cancer-specific death following conservative treatment (p = 0.009). In multivariate models, however, ZNF132 did not add significant independent value to established prognostic factors. Finally, bisulfite sequencing revealed frequent promoter hypermethylation of ZNF132 in both PC cell lines and PC tissue samples, indicating that ZNF132 is epigenetically silenced in PC. In summary, our results show that downregulation of ZNF132 is associated with aggressive PC and furthermore identify ZNF132 as a new candidate methylation marker for PC.

Abstract

This study investigates the expression and biomarker potential of zinc finger protein 132 (ZNF132) in prostate cancer (PC) by transcriptional profiling and immunohistochemical analysis of tissue microarrays, including tumor specimens from 615 radical prostatectomy (RP) patients and 199 conservatively treated patients. Primary clinical endpoints were time to PSA recurrence and cancer-specific death, respectively. Compared to normal prostate epithelial cells from men without PC, ZNF132 transcript levels were significantly reduced in PC cells from patients with localized PC and further downregulated in metastatic PC. Likewise, ZNF132 protein expression was significantly lower in primary tumors from patients with metastatic compared to localized PC and further reduced in castrate-refractory PC, indicating that ZNF132 downregulation correlates with disease progression. Reduced ZNF132 immunoreactivity was significantly associated with high Gleason score and advanced T stage in both PC patient cohorts. By univariate analysis, no/weak ZNF132 staining was a significant adverse predictor of PSA recurrence after RP (p = 0.024) and cancer-specific death following conservative treatment (p = 0.009). In multivariate models, however, ZNF132 did not add significant independent value to established prognostic factors. Finally, bisulfite sequencing revealed frequent promoter hypermethylation of ZNF132 in both PC cell lines and PC tissue samples, indicating that ZNF132 is epigenetically silenced in PC. In summary, our results show that downregulation of ZNF132 is associated with aggressive PC and furthermore identify ZNF132 as a new candidate methylation marker for PC.

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11 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:19 Oct 2011 12:24
Last Modified:05 Apr 2016 15:02
Publisher:Wiley-Blackwell
ISSN:0020-7136
Publisher DOI:https://doi.org/10.1002/ijc.26097
PubMed ID:21445975

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