Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha

Abstract

BackgroundThe ZNF217 gene, encoding a C2H2 zinc finger protein, is located at 20q13 and found amplified and overexpressed in greater than 20% of breast tumors. Current studies indicate ZNF217 drives tumorigenesis, yet the regulatory mechanisms of ZNF217 are largely unknown. Because ZNF217 associates with chromatin modifying enzymes, we postulate that ZNF217 functions to regulate specific gene signaling networks. Here, we present a large-scale functional genomic analysis of ZNF217, which provides insights into the regulatory role of ZNF217 in MCF7 breast cancer cells.ResultsChIP-seq analysis reveals that the majority of ZNF217 binding sites are located at distal regulatory regions associated with the chromatin marks H3K27ac and H3K4me1. Analysis of ChIP-seq transcription factor binding sites shows clustering of ZNF217 with FOXA1, GATA3 and ERalpha binding sites, supported by the enrichment of corresponding motifs for the ERalpha-associated cis-regulatory sequences. ERalpha expression highly correlates with ZNF217 in lysates from breast tumors (n = 15), and ERalpha co-precipitates ZNF217 and its binding partner CtBP2 from nuclear extracts. Transcriptome profiling following ZNF217 depletion identifies differentially expressed genes co-bound by ZNF217 and ERalpha; gene ontology suggests a role for ZNF217-ERalpha in expression programs associated with ER+ breast cancer studies found in the Molecular Signature Database. Data-mining of expression data from breast cancer patients correlates ZNF217 with reduced overall survival.ConclusionsOur genome-wide ZNF217 data suggests a functional role for ZNF217 at ERalpha target genes. Future studies will investigate whether ZNF217 expression contributes to aberrant ERalpha regulatory events in ER+ breast cancer and hormone resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-520) contains supplementary material, which is available to authorized users.

An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

“…Additionally, we have shown that the estrogen-induced miRNA, miR-503, targets the 3 ′ -UTR of ZNF217 and that while miR-503 is induced in response to estrogen, the oncogene ZNF217 is reduced. In support of this relationship, data from breast cancer patient cohorts show that high expression of ZNF217 is associated with worse survival (Gyorffy et al 2009;Frietze et al 2014), while high expression of miR-503 is associated with improved survival (Antonov 2011;Lyng et al 2012;Antonov et al 2013). Furthermore, while this manuscript was under review, another study was published demonstrating that the GATA3-driven expression of miR-503 represses ZNF217 in prostate cancer (Jiang et al 2016).…”

“…2C)-all critical genes to the etiology of breast cancer (Sørlie et al 2001;Usary et al 2004;Oh et al 2006;Cohen et al 2015). ZNF217, a no- (Cohen et al 2015) and has been identified as a biomarker of poor survival in patients with Luminal A (ER+) breast tumors (Frietze et al 2014). Approximately 40% of the genes in the repressed class were previously identified as down-regulated at 24 h after estrogen stimulation (Jagannathan and Robinson-Rechavi 2011).…”

“…ZNF217 binds to many of the same promoters as the three transcription factors that coordinate the overall response to estrogen stimulation (ERα, GATA3, and FOXA1) (Kong et al 2011;Frietze et al 2014). Additionally, the C terminus of ZNF217 physically binds to the hinge domain of ERα and enhances recruitment of ERα to EREs (Nguyen et al 2014).…”

“…S7A; Gyorffy et al 2009;Frietze et al 2014) and high expression of miR-503 (Supplemental Fig. S7B; Antonov 2011;Lyng et al 2012;Antonov et al 2013) in breast cancer is significantly associated with improved survival (P = 0.038 for ZNF217 and P = 0.000437 for miR-503).…”

“…Overall survival of ER+ breast cancer patients based on ZNF217 high/low status was evaluated using the Kaplan-Meier plotter (http://kmplot.com/; Gyorffy et al 2009;Frietze et al 2014). The following parameters were used on the breast cancer database: Affy ID = 203739_at; survival = OS; split patients by = median; ER status = ER positive; derive ER status from gene expression data = checked; database version = 2014 (n = 4142).…”