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ZNF714 – a novel oncogene in lung cancer cells

ABSTRACT: The emerging data indicate that many KRAB-ZNF factors belonging to a large gene family may be involved in carcinogenesis. Our previous study identified ZNF714, a KRAB-ZNF gene of unknown function, as commonly overexpressed in many tumors, pointing to its hypothetical oncogenic role. We knocked down ZNF714 gene expression in two lung cancer cell lines: H2073 (lung adenocarcinoma) and SKMES (squamous cell carcinoma), and subjected them to methylation microarray analysis. We identified 45k DMRs in H2073 and 75k DMRs in SKMES. In both cell lines, the majority of changes (both hypo- and hypermethylation) occurred within gene bodies and promoter regions (TSS1500 and TSS200). The only visible altered methylation pattern indicated more frequent hypomethylation within the promoter region in both shZNF714 cell lines. We correlated those results with our RNA-seq analysis and identified target genes simultaneously overexpressed and unmethylated in cells with knocked-down ZNF714 expression. We identified 54 genes in H2073 and 36 genes in SKMES that met our criteria. Interestingly, several of those genes have documented tumor-suppressive functions, further supporting our in vitro results demonstrating an oncogenic role of ZNF714.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238088 | GEO | 2023/11/22

REPOSITORIES: GEO

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Project description:KAP1 is overexpressed in breast cancer. To determine KAP1 regulated genes, we performed microarray analysis of gene expression in KAP1 depleted breast cancer cells MDA-MB-231LN. The transcriptional regulator TRIM28/KAP1 plays an important role in development, stem cell self-renewal, chromatin organization and the DNA damage response. KAP1 is an essential co-repressor for KRAB zinc finger proteins (KRAB-ZNFs). Though KRAB-ZNFs represent the largest family of human transcription factors, their biological functions are largely unknown. Using the conserved zinc fingers linker region (ZnFL) as antigen, we have developed a ZnFL antibody that recognizes multiple KRAB-ZNFs. We showed that KAP1 and many KRAB-ZNFs were overexpressed in human breast cancers and breast cancer cell lines. In addition, an active SUMOylated form of KAP1 was markedly increased in breast cancer cells. Furthermore, KAP1 depletion in breast cancer cell lines reduced cell proliferation and inhibited tumor growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. KAP1 knockdown led to down-regulation of genes previously linked to tumor progression and metastasis, including PTGS2/COX2, EREG, CD44, MMP1 and MMP2. Interestingly, KAP1 depletion or genomic deletion led to dramatic down-regulation of multiple KRAB-ZNF proteins due in part to their increased degradation. KAP1-dependent stabilization of KRAB-ZNFs required a direct KRAB-ZNF-KAP1 interaction. These results establish KAP1 as a positive regulator of multiple KRAB-ZNFs and an important factor in the development of breast cancer. 7 total samples were analyzed. Stable sublines of MDA-MB-231LN cells expressing control non-targeting shRNA (Scr, 3 biological replicates) and two different shRNAs against KAP1 (KAP1-3, 2 biological replicates and KAP1-4, 2 biological replicates) from doxycycline-inducible pTRIPZ vector were cultured in the presence of 0.5 ug/ml doxycycline for 7 days to induce shRNA expression. Cells were lysed and total RNA was isolated using mirVana miRNA isolation kit (Ambion) in the WVU Genomics Core Facility.

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ZNF714 – a novel oncogene in lung cancer cells

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