title: Downregulation of zinc finger protein 132 in prostate cancer is associated with aberrant promoter hypermethylation and poor prognosis.
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.
authors: Department of Molecular Medicine, Aarhus University Hospital, Skejby, Aarhus, Denmark.
authors: Mette Opstrup
authors: MO
authors: Abildgaard
authors: Michael
authors: M
authors: Borre
authors: Martin Mørck
authors: MM
authors: Mortensen
authors: Benedicte P
authors: BP
authors: Ulhøi
authors: Niels
authors: N
authors: Tørring
authors: Peter
authors: P
authors: Wild
authors: Helle
authors: H
authors: Kristensen
authors: Francisco
authors: F
authors: Mansilla
authors: Peter D
authors: PD
authors: Ottosen
authors: Lars
authors: L
authors: Dyrskjøt
authors: Torben F
authors: TF
authors: Ørntoft
authors: Karina Dalsgaard
authors: KD
authors: Sørensen
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C570257:ZNF132 protein, human