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Expression of polycomb targets predicts breast cancer prognosis.

ABSTRACT: Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype.

SUBMITTER: Jene-Sanz A

PROVIDER: S-EPMC3811872 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Expression of polycomb targets predicts breast cancer prognosis.

Jene-Sanz Alba A Váraljai Renáta R Vilkova Alexandra V AV Khramtsova Galina F GF Khramtsov Andrey I AI Olopade Olufunmilayo I OI Lopez-Bigas Nuria N Benevolenskaya Elizaveta V EV

Molecular and cellular biology 20130805 19

Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27 ...[more]

PMID: 23918806

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Project description:BackgroundTo date, breast cancer remains the most common malignant tumor in women. In recent years, a growing number of studies on polycomb proteins have been conducted. The Ring finger protein1 (RING1), an essential component of the polycomb family of proteins, plays vital roles in the tumorigenesis of various cancer types. However, further research is required in determining RING1 expression and prognostic value in breast cancer.MethodRING1 expression level in multiple cancer types was evaluated using the XENA and UALCAN databases. Real-time quantitative PCR (real-time qPCR) and immunohistochemistry (IHC) were used to confirm this expression. The prognostic value was analyzed using our follow-up data and the Kaplan-Meier plotter website. RING1 co-expressed genes and its promoter methylation level were calculated using the cBioPortal and UALCAN online tools. The gene ontology (GO) and the Kyoto encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed using the DAVID online analysis tool.ResultRING1 expression was upregulated in CHOL (Bile Duct Cancer), ESCA (Esophageal Cancer), LIHC (Liver Cancer), and PCPG (Pheochromocytoma & Paraganglioma). However, its expression level was decreased in COAD (Colon Cancer), KICH (Kidney Chromophobe), KIRP (kidney papillary cell carcinoma), THCA (Thyroid Cancer), and BRCA (Breast carcinoma). RING1 low expression is an unfavorable prognostic factor in many cancer patients, especially in breast cancer patients. For breast cancer, the IHC result showed that RING1 protein expression significantly and negatively correlates with tumor size (P = 0.029), LNM (P = 0.017), TNM stage (P = 0.016), ER (P = 0.005), Ki67 (P = 0.015), and p53 status (P = 0.034). Moreover, the multivariate Cox regression model indicated that RING1 (P = 0.038) and ER (P = 0.029) expressions were independent prognostic markers for breast cancer. RING1 co-expressed genes were selected and included HDAC10, PIN1, CDK3, BAX, and BAD. GO analysis and KEGG pathway analyses revealed that RING1 related genes, were mainly enriched in "regulation of transcription", "apoptotic process", "protein transport", "protein binding", "Notch signaling pathway", and "Homologous recombination".ConclusionRING1 expression was downregulated in breast cancer, and its low expression was associated with worse disease outcomes. RING1 may act as a new prognostic biomarker for breast cancer.

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Expression of polycomb targets predicts breast cancer prognosis.

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Expression of polycomb targets predicts breast cancer prognosis.

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