Abstract
In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.
Highlights
Gene expression in malignant tumors may be affected by genetic and epigenetic changes
A statistically significant downregulation of zink finger protein 677 (ZNF677) expression in TU compared to non-malignant lung tissue (NL) samples was observed in dataset E-GEOD-18842 (Bonferroni adjusted p-value = 0.00003) and similar results were seen in dataset E-GEOD-19188 (Bonferroni adjusted p-value = 0.0007)
To confirm tumor-specific downregulation of ZNF677 expression observed by gene expression microarray analyses, we compared ZNF677 RNA-seq expression values in TU and NL samples of LUAD and LUSC datasets obtained from the Cancer Browser database [17]
Summary
Gene expression in malignant tumors may be affected by genetic and epigenetic changes. DNA methylation (referred to as methylation) which is an epigenetic change was identified as alternative mechanism to transcriptionally regulate expression of certain genes. Methylation describes the covalent addition of a methyl group to the 5′ carbon of cytosine bases within cytosine-guanine (CpG) dinucleotides located at high density in CpG islands (CGI) leading to transcriptional gene silencing [4]. It may be reversible by DNA methyltransferase inhibitors like 5-aza-2′-deoxycytidine www.impactjournals.com/oncotarget (Aza-dC) and a synergistic effect in upregulation of gene expression together with histone deacetylase inhibitors like trichostatin A (TSA) was described [5, 6]. We recently identified ~500 tumor- methylated genes when we used a genome-wide approach to search for methylated genes in NSCLC patients [7]
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