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 5 0.024) and cancer-specific death following conservative treatment (p 5 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.

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

“…An effect mediated by β-catenin is given additional support by our transcriptome analysis. In addition, based on our findings, CHD8 may also contribute to malignant transformation indirectly through its effects on other genes, which were found to be differentially expressed in this study and have been implicated in malignant transformation, such as SMARCA4 , POU4F1 , ARMCX1 , HMAG2 , DCC , and ZNF132 (Additional file 4: Table S2) [116, 117]. Several of the differentially expressed ncRNAs we show on Table 2 have also been found to be associated with cancer development, including TERC , which codes for the RNA component of telomerase; telomere shortening is a feature of malignant transformation and aging [118].…”

Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma

“…The role of these proteins in HNSCC carcinogenesis remains unclear. However, we know that ZNF132 has been identified as epigenetically silenced by DNA hypermethylation in prostate cancer, and that reduced ZNF132 immunoreactivity was significantly associated with high Gleason score and advanced T stage in prostate cancer patient cohorts (29). Furthermore, hypermethylation of ZNF154 has recently been identified as part of a panel of early detection biomarkers in DNA from voided urine of bladder cancer patients, along with two other hypermethylated genes (HOXA9 and EOMES) identified in our HNSCC patients (30).…”

Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer

“…The CT cohort TMA (Abildgaard et al , 2012) contained tumour specimens from 111 PC patients diagnosed with clinically localised PC from 1979 to 1983 in Aarhus County, Denmark (Table 1). This cohort has been described previously in detail (Borre et al , 1997).…”