GATA6

Gene Summary

Gene:GATA6; GATA binding protein 6
Location:18q11.2
Summary:This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor GATA-6
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (56)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Theca Cells
  • Transcription
  • Adenocarcinoma
  • Polymerase Chain Reaction
  • Receptors, Progesterone
  • GATA4 Transcription Factor
  • Young Adult
  • Ovarian Cancer
  • Gene Silencing
  • Cell Differentiation
  • Rectal Cancer
  • DNA Methylation
  • Promoter Regions
  • Oligonucleotide Array Sequence Analysis
  • Transcription Factors
  • MicroRNAs
  • siRNA
  • Transforming Growth Factor beta
  • Cell Proliferation
  • GATA5 Transcription Factor
  • Messenger RNA
  • Neoplastic Cell Transformation
  • DNA-Binding Proteins
  • ras Proteins
  • Sequence Deletion
  • Tetraspanins
  • Stomach Cancer
  • Chromosome 18
  • Cancer Gene Expression Regulation
  • Pancreatic Cancer
  • Gene Expression Profiling
  • GATA6 Transcription Factor
  • Lung Cancer
  • Polycystic Ovary Syndrome
  • Childhood Cancer
  • Biomarkers, Tumor
  • Signal Transduction
  • Zinc Fingers
  • Tumor Suppressor Gene
  • Adrenocortical Cancer
  • Immunohistochemistry
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GATA6 (cancer-related)

Kondratyeva LG, Sveshnikova AA, Grankina EV, et al.
Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial-mesenchymal transition.
Dokl Biochem Biophys. 2016; 469(1):257-9 [PubMed] Related Publications
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1, and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFβ1.

Murphy SJ, Hart SN, Halling GC, et al.
Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease.
Cancer Res. 2016; 76(3):749-61 [PubMed] Free Access to Full Article Related Publications
Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFβ signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression.

Antontseva EV, Matveeva MY, Bondar NP, et al.
Regulatory single nucleotide polymorphisms at the beginning of intron 2 of the human KRAS gene.
J Biosci. 2015; 40(5):873-83 [PubMed] Related Publications
There are two regulatory single nucleotide polymorphisms (rSNPs) at the beginning of the second intron of the mouse K-ras gene that are strongly associated with lung cancer susceptibility. We performed functional analysis of three SNPs (rs12228277: T greater than A, rs12226937: G greater than A, and rs61761074: T greater than G) located in the same region of human KRAS. We found that rs12228277 and rs61761074 result in differential binding patterns of lung nuclear proteins to oligonucleotide probes corresponding two alternative alleles; in both cases, the transcription factor NF-Y is involved. G greater than A substitution (rs12226937) had no effect on the binding of lung nuclear proteins. However, all the nucleotide substitutions under study showed functional effects in a luciferase reporter assay. Among them, rs61761074 demonstrated a significant correlation with allele frequency in non-small-cell lung cancer (NSCLC). Taken together, the results of our study suggest that a T greater than G substitution at nucleotide position 615 in the second intron of the KRAS gene (rs61761074) may represent a promising genetic marker of NSCLC.

Song Y, Tian T, Fu X, et al.
GATA6 is overexpressed in breast cancer and promotes breast cancer cell epithelial-mesenchymal transition by upregulating slug expression.
Exp Mol Pathol. 2015; 99(3):617-27 [PubMed] Related Publications
Metastasis is the leading cause of death in breast cancer (BC) patients. However, until now, the mechanisms of BC metastasis remain elusive. GATA6 is a member of the GATA transcription factor family that plays critical regulatory roles in tissue development, which has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in BC remain unclear. Here we show that GATA6 is elevated in BC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of GATA6 was associated with decreased overall survival of BC patients. Overexpression of GATA6 in BC cells increased epithelial-mesenchymal transition. In contrast, silencing GATA6 in aggressive BC cells inhibited this process. Mechanistically, we found GATA6 exerts its function through active slug transcription. Slug knockdown blocked the GATA6-driven EMT. Furthermore, slug expression in human BC is positively correlated with GATA6 expression. Our results, for the first time, portray a pivotal role of GATA6 in regulating metastatic behaviors of BC cells, suggesting GATA6 is a potential therapeutic target in metastatic BCs.

Kim JS, Kurie JM, Ahn YH
BMP4 depletion by miR-200 inhibits tumorigenesis and metastasis of lung adenocarcinoma cells.
Mol Cancer. 2015; 14:173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA-200 (miR-200) suppresses the epithelial-mesenchymal transition of various cancer cells, including lung adenocarcinoma cells. We found that bone morphogenetic protein 4 (BMP4) was decreased in miR-200-overexpressing cells and epithelial-like lung cancer cells. In this study, we investigated the mechanism and role of BMP4 depletion by miR-200 in murine lung adenocarcinoma cells.
METHODS: BMP4 expression levels in murine lung cancer cells were measured by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Promoter and 3'-untranslated region (UTR) luciferase reporter assays were performed to discover the mechanism of regulation of BMP4 by miR-200. Murine lung cancer cells were transfected with Bmp4 shRNAs, which were then injected into syngeneic mice to measure their tumorigenic and metastatic potential and cultured on Matrigel to study the influence of BMP4 on 3-D acinus formation.
RESULTS: miR-200 down-regulated BMP4 via direct targeting of the GATA4 and GATA6 transcription factors that stimulate Bmp4 transcription. BMP4 up-regulated JAG2, an upstream factor of miR-200; therefore, JAG2, miR-200, and BMP4 form a regulatory loop. Bmp4 knockdown suppressed cancer cell growth, migration, and invasion and inhibited tumorigenesis and metastasis of lung cancer cells when injected into syngeneic mice. In addition, BMP4 was required for normal acinus formation in Matrigel 3-D culture of murine lung cancer cells, which may be mediated by MYH10, a downstream target of BMP4.
CONCLUSION: BMP4 functions as a pro-tumorigenic factor in a murine lung cancer model, and its transcription is regulated by miR-200 and GATA4/6. Thus, we propose that BMP4 and its antagonists may be suitable therapeutic targets for the treatment of lung cancer.

Kawasaki Y, Matsumura K, Miyamoto M, et al.
REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.
Sci Rep. 2015; 5:14291 [PubMed] Free Access to Full Article Related Publications
The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR5 and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG4, a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG4 is downregulated by overexpression of miR-363, which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG4 enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG4) and genes required for their clonogenicity (LGR5), and that the miR-363-GATA6-REG4/LGR5 signaling cascade promotes the tumorigenicity of colon cancer cells.

Becker J, May A, Gerges C, et al.
Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma.
Cancer Med. 2015; 4(11):1700-4 [PubMed] Free Access to Full Article Related Publications
The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10(-5) ) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.

Xu X, Ge S, Jia R, et al.
Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6.
Oncol Rep. 2015; 33(6):2789-96 [PubMed] Related Publications
Previous findings showed that miR-181b is upregulated under hypoxic conditions in retinoblastoma cells. Since hypoxia is a common feature of retinoblastoma that affects tumor progression as well as tumor therapy, in the present study, we investigated the regulatory mechanism of miR-181b under hypoxic conditions, and examined the role of miR-181b in retinoblastoma responses to hypoxia (chemoresistance and angiogenesis) and possible downstream genes. The level of hypoxia-inducible factor-1α (HIF-1α) and miR-181b was detected to examine the link between them. Tube formation and cell cytotoxicity assays were used to clarify the effects of miR-181b on hypoxic responses of retinoblastoma cells. Bioinformatics analysis was performed to predict potential targets of miR-181b and western blotting was used to verify these targets. The results showed a significantly increased expression of HIF-1α in hypoxia-treated retinoblastoma cells. Downregulation of HIF-1α using a small-interfering RNA (siRNA) knockdown technology did not decrease the expression of miR-181b. Through gain- and loss-of-function studies, miR-181b was demonstrated to significantly stimulate the ability of capillary tube formation of endothelial cells. Programmed cell death-10 (PDCD10) and GATA binding protein 6 (GATA6) were identified as the target genes of miR‑181b. To the best of our knowledge, results of the present study provide the first evidence that miR-181b was upregulated by hypoxia in retinoblastoma in an HIF-1α-independent manner. miR-181b increased tumor angiogenesis of retinoblastoma cells. Additionally, miR-181b exerts its angiogenic function, at least in part, by inhibiting PDCD10 and GATA6. Thus, it is a new potentially useful therapeutic target for retinoblastoma.

Wong HK, Gibson H, Hake T, et al.
Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome.
J Invest Dermatol. 2015; 135(8):2084-92 [PubMed] Related Publications
The Sézary Syndrome (SS) is an aggressive CD4+ leukemic variant of cutaneous T-cell lymphoma. Epigenetic modification of cancer cell genome is often linked to the expression of important cancer-related genes. Here we addressed the hypothesis that, in SS, DNA hypomethylation is involved in upregulation of PLS3, GATA6, and TWIST1, genes that are undetected in normal lymphocytes. Pyrosequencing analysis of CpG rich regions, and CpG dinucleotides within the 5' regulatory regions, confirmed hypomethylation of all three genes in SS, compared with controls. We then studied how methylation regulates PLS3 transcription in vitro using PLS3-negative (Jurkat) and PLS3-positive (HT-1080) cell lines. Treatment with the hypomethylating agent 5-azacytidine induced PLS3 expression in Jurkat cells and in vitro methylation of the cloned PLS3 promoter suppressed luciferase expression in HT-1080 cells. In conclusion, we show that promoter hypomethylation is associated with PLS3, GATA6, and TWIST1 overexpression in SS CD4+ T cells and that methylation can regulate PLS3 expression in vitro. The mechanisms of DNA hypomethylation in vivo and the functional role of PLS3, TWIST1, and GATA6 in SS are being investigated.

Majchrzak-Celińska A, Paluszczak J, Szalata M, et al.
DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade.
J Cancer Res Clin Oncol. 2015; 141(9):1593-601 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Although meningiomas are common central nervous system tumors, the biomarkers allowing early diagnosis and progression are still needed. The aim of this study was to evaluate the methylation status of 12 cancer-related genes, namely ERCC1, hMLH1, ATM, CDKN2B (p15INK4B), p14ARF, CDKN2A (p16INK4A), RASSF1A, RUNX3, GATA6, NDRG2, PTEN, and RARβ, in 44 meningioma samples of WHO grade I and II.
METHODS: All genes were analyzed using methylation-specific polymerase chain reaction, while pyrosequencing (PSQ) was used to study NDRG2 promoter methylation.
RESULTS: The most frequently methylated genes in both types of meningiomas were p14ARF, RASSF1A, and p15INK4B. RUNX3, GATA6, and p16INK4A were methylated to a lesser extent, whereas ATM and RARβ were found to be methylated in a marginal number of patients. The ERCC1, hMLH1, NDRG2, and PTEN genes were unmethylated in all cases. Although tumors of the same grade according to WHO criteria had different genes methylated, the number of methylated genes for each individual patient was low. RUNX3 methylation significantly correlated with meningioma WHO grade, therefore, can be considered as a potential indicator of tumor aggressiveness. The sequence of NDRG2 chosen for PSQ analysis was found methylated in the majority of meningiomas; however, the methylation level was only slightly elevated as compared to non-cancerous brain.
CONCLUSIONS: Overall, the results of this study confirm that DNA methylation plays an important role in the pathogenesis of meningiomas. Further investigations, particularly concerning RUNX3 methylation, are necessary in order to assess the clinical usefulness of the methylation analysis of the studied genes.

Martinelli P, Madriles F, Cañamero M, et al.
The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice.
Gut. 2016; 65(3):476-86 [PubMed] Related Publications
BACKGROUND AND AIMS: Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinar-ductal metaplasia, which is considered an initial step of mutant KRas-driven carcinogenesis. Therefore, the Gata6-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis.
DESIGN: We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of KRas(G12V)-driven tumours
RESULTS: We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to KRas(G12V), thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of KRas(G12V)-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic Gata6-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR.
CONCLUSIONS: We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.

Majchrzak-Celińska A, Paluszczak J, Szalata M, et al.
The methylation of a panel of genes differentiates low-grade from high-grade gliomas.
Tumour Biol. 2015; 36(5):3831-41 [PubMed] Related Publications
Epigenetic changes play an important role in the pathogenesis of gliomas and have the potential to become clinically useful biomarkers. The aim of this study was the evaluation of the profile of promoter methylation of 13 genes selected based on their anticipated diagnostic and/or prognostic value. Methylation-specific PCR (MSP) was used to assess the methylation status of MGMT, ERCC1, hMLH1, ATM, CDKN2B (p15INK4B), p14ARF, CDKN2A (p16INK4A), RASSF1A, RUNX3, GATA6, NDRG2, PTEN, and RARβ in a subset of 95 gliomas of different grades. Additionally, the methylation status of MGMT and NDRG2 was analyzed using pyrosequencing (PSQ). The results revealed that the methylation index of individual glioma patients correlates with World Health Organization (WHO) tumor grade and patient's age. RASSF1A, RUNX3, GATA6, and MGMT were most frequently methylated, whereas the INK4B-ARF-INK4A locus, PTEN, RARβ, and ATM were methylated to a lesser extent. ERCC1, hMLH1, and NDRG2 were unmethylated. RUNX3 methylation correlated with WHO tumor grade and patient's age. PSQ confirmed significantly higher methylation levels of MGMT and NDRG2 as compared with normal, non-cancerous brain tissue. To conclude, DNA methylation of a whole panel of selected genes can serve as a tool for glioma aggressiveness prediction.

Pavlov K, Honing J, Meijer C, et al.
GATA6 expression in Barrett's oesophagus and oesophageal adenocarcinoma.
Dig Liver Dis. 2015; 47(1):73-80 [PubMed] Related Publications
BACKGROUND: Barrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia-dysplasia-carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma.
AIM: To study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma.
METHODS: Two retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease-free survival.
RESULTS: The percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P < 0.001) and high-grade dysplasia (82%, P = 0.005). GATA6 expression was not associated with overall or disease-free survival in oesophageal adenocarcinoma patients (P = 0.599 and P = 0.700 respectively).
CONCLUSION: GATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma.

Hermann PC, Sancho P, Cañamero M, et al.
Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.
Gastroenterology. 2014; 147(5):1119-33.e4 [PubMed] Related Publications
BACKGROUND & AIMS: Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC.
METHODS: We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors.
RESULTS: Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program.
CONCLUSIONS: In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.

Chia NY, Deng N, Das K, et al.
Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.
Gut. 2015; 64(5):707-19 [PubMed] Related Publications
OBJECTIVE: Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications.
DESIGN: KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice.
RESULTS: KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs.
CONCLUSIONS: KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.

Whissell G, Montagni E, Martinelli P, et al.
The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression.
Nat Cell Biol. 2014; 16(7):695-707 [PubMed] Related Publications
Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with β-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.

Cai WS, Shen F, Li JL, et al.
Activated protease receptor-2 induces GATA6 expression to promote survival in irradiated colon cancer cells.
Arch Biochem Biophys. 2014; 555-556:28-32 [PubMed] Related Publications
BACKGROUND AND AIMS: The resistance to irradiation is common and a great drawback in the treatment of cancer with radiotherapy; the underlying mechanism is unclear. GATA binding protein 6 (GATA6) is associated with the pathogenesis of cancer. This study aims to investigate the role of GATA6 on compromising irradiation effect on HT55 and HT29 cells, 2 colorectal cancer cell lines.
METHODS: Human colon cancer cell lines, HT55 and HT29 cells, were treated with irradiation in the culture. Apoptosis of HT55 and HT29 cells was determined by flow cytometry. The expression of PAR2 and GATA6 in HT55 and HT29 cells was analyzed by real time RT-PCR and Western blotting. The gene silence and gene over expression were employed to observe the effect of GATA6 on p53 expression in HT55 and HT29 cells.
RESULTS: The results showed that HT55 and HT29 cells expressed protease-activated receptor-2 (PAR2). Irradiation induced 38.6% HT55 cell and 33.8% HT29 cell apoptosis, which reduced to 4.2% and 5.6%, respectively after activation of PAR2. Exposure to irradiation increased the expression of GATA6; the latter played a critical role in suppression of p53 expression in HT55 and HT29 cells. Inhibition of GATA6 significantly increased the effect of irradiation on HT55 and HT29 cells.
CONCLUSIONS: Activation of PAR2 compromises the effect of irradiation on inducing colorectal cancer cell apoptosis, which can be prevented by inhibition of GATA6 expression.

Yang Y, Ahn YH, Chen Y, et al.
ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism.
J Clin Invest. 2014; 124(6):2696-708 [PubMed] Free Access to Full Article Related Publications
Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition (EMT) are typically prone to metastasis and drug resistance and contribute to a poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, and mediators of ZEB1 represent potential therapeutic targets for metastasis suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted (PI3K-targeted) therapy suppresses metastasis in a mouse model of Kras/Tp53-mutant lung adenocarcinoma that develops metastatic disease due to high expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, ZEB1-dependent derepression of the miR-200 and miR-183 target friend of GATA 2 (FOG2) enhanced GATA3-induced expression of the p110α catalytic subunit of PI3K. Knockdown of FOG2, p110α, and RHEB ameliorated invasive and metastatic propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal differentiation, suggesting that mesenchymal differentiation and invasion are distinct and separable processes. Together, these results indicate that ZEB1 sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted therapy and suggest that treatments to selectively modify the metastatic behavior of mesenchymal tumor cells are feasible and may be of clinical value.

Sulahian R, Casey F, Shen J, et al.
An integrative analysis reveals functional targets of GATA6 transcriptional regulation in gastric cancer.
Oncogene. 2014; 33(49):5637-48 [PubMed] Free Access to Full Article Related Publications
Lineage-restricted transcription factors (TFs) are frequently mutated or overexpressed in cancer and contribute toward malignant behaviors; however, the molecular bases of their oncogenic properties are largely unknown. As TF activities are difficult to inhibit directly with small molecules, the genes and pathways they regulate might represent more tractable targets for drug therapy. We studied GATA6, a TF gene that is frequently amplified or overexpressed in gastric, esophageal and pancreatic adenocarcinomas. GATA6-overexpressing gastric cancer cell lines cluster in gene expression space, separate from non-overexpressing lines. This expression clustering signifies a shared pathogenic group of genes that GATA6 may regulate through direct cis-element binding. We used chromatin immunoprecipitation and sequencing (ChIP-seq) to identify GATA6-bound genes and considered TF occupancy in relation to genes that respond to GATA6 depletion in cell lines and track with GATA6 mRNA (synexpression groups) in primary gastric cancers. Among other cellular functions, GATA6-occupied genes control apoptosis and govern the M-phase of the cell cycle. Depletion of GATA6 reduced the levels of the latter transcripts and arrested cells in G2 and M phases of the cell cycle. Synexpression in human tumor samples identified likely direct transcriptional targets substantially better than consideration only of transcripts that respond to GATA6 loss in cultured cells. Candidate target genes responded to the loss of GATA6 or its homolog GATA4 and even more to the depletion of both proteins. Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. Thus, many downstream effects occur indirectly through other TFs and GATA6 activity in gastric cancer is partially redundant with GATA4. This integrative analysis of locus occupancy, gene dependency and synexpression provides a functional signature of GATA6-overexpressing gastric cancers, revealing both limits and new therapeutic directions for a challenging and frequently fatal disease.

Brown KC, Perry HE, Lau JK, et al.
Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.
J Biol Chem. 2013; 288(46):33049-59 [PubMed] Free Access to Full Article Related Publications
Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.

Babic AM, Jang S, Nicolov E, et al.
Culture of mouse amniotic fluid-derived cells on irradiated STO feeders results in the generation of primitive endoderm cell lines capable of self-renewal in vitro.
Cells Tissues Organs. 2013; 198(2):111-26 [PubMed] Free Access to Full Article Related Publications
The cells present in amniotic fluid (AF) are currently used for prenatal diagnosis of fetal anomalies but are also a potential source of cells for cell therapy. To better characterize putative progenitor cell populations present in AF, we used culture conditions that support self-renewal to determine if these promoted the generation of stable cell lines from AF-derived cells (AFC). Cells isolated from E11.5 mouse were cultured on irradiated STO fibroblast feeder layers in human embryonic germ cell derivation conditions. The cultures grew multicellular epithelial colonies that could be repropagated from single cells. Reverse transcription semiquantitative polymerase chain reaction of established cell lines revealed that they belonged to the extraembryonic endoderm (ExEn) expressing high levels of Gata6, Gata4, Sox17, Foxa2 and Sox7 mRNA. Hierarchical clustering based on the whole transcriptome expression profile of the AFC lines (AFCL) shows significant correlation between transcription profiles of AFCL and blastocyst-derived XEN, an ExEn cell line. In vitro differentiation of AFCL results in the generation of cells expressing albumin and α-fetoprotein (AFP), while intramuscular injection of AFCL into immunodeficient mice produced AFP-positive tumors with primitive endodermal appearance. Hence, E11.5 mouse AF contains cells that efficiently produce XEN lines. These AF-derived XEN lines do not spontaneously differentiate into embryonic-type cells but are phenotypically stable and have the capacity for extensive expansion. The lack of requirement for reprogramming factors to turn AF-derived progenitor cells into stable cell lines capable of massive expansion together with the known ability of ExEn to contribute to embryonic tissue suggests that this cell type may be a candidate for banking for cell therapies.

Parviainen H, Schrade A, Kiiveri S, et al.
Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness.
Pathol Res Pract. 2013; 209(8):503-9 [PubMed] Free Access to Full Article Related Publications
Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples⋅ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.

Bhattacharyya S, Yu Y, Suzuki M, et al.
Genome-wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer.
Nucleic Acids Res. 2013; 41(16):e157 [PubMed] Free Access to Full Article Related Publications
5-hydroxymethylcytosine (5-hmC) is a recently discovered epigenetic modification that is altered in cancers. Genome-wide assays for 5-hmC determination are needed as many of the techniques for 5-methylcytosine (5-mC) determination, including methyl-sensitive restriction digestion and bisulfite sequencing cannot distinguish between 5-mC and 5-hmC. Glycosylation of 5-hmC residues by beta-glucosyl transferase (β-GT) can make CCGG residues insensitive to digestion by MspI. Restriction digestion by HpaII, MspI or MspI after β-GT conversion, followed by adapter ligation, massive parallel sequencing and custom bioinformatic analysis allowed us determine distribution of 5-mC and 5-hmC at single base pair resolution at MspI restriction sites. The resulting HpaII tiny fragment Enrichment by Ligation-mediated PCR with β-GT (HELP-GT) assay identified 5-hmC loci that were validated at global level by liquid chromatography-mass spectrometry (LC-MS) and the locus-specific level by quantitative reverse transcriptase polymerase chain reaction of 5-hmC pull-down DNA. Hydroxymethylation at both promoter and intragenic locations correlated positively with gene expression. Analysis of pancreatic cancer samples revealed striking redistribution of 5-hmC sites in cancer cells and demonstrated enrichment of this modification at many oncogenic promoters such as GATA6. The HELP-GT assay allowed global determination of 5-hmC and 5-mC from low amounts of DNA and with the use of modest sequencing resources. Redistribution of 5-hmC seen in cancer highlights the importance of determination of this modification in conjugation with conventional methylome analysis.

Chen WB, Huang FT, Zhuang YY, et al.
Silencing of GATA6 suppresses SW1990 pancreatic cancer cell growth in vitro and up-regulates reactive oxygen species.
Dig Dis Sci. 2013; 58(9):2518-27 [PubMed] Related Publications
BACKGROUND/AIMS: Pancreatic cancer has the worst prognosis of any gastrointestinal cancer with a mortality rate approaching its incidence. Previous studies have indicated that GATA6 plays a key role in organ development and function, and that abnormal expression of GATA6 may induce tumorigenesis. Meanwhile, it has been reported that generation of reactive oxygen species contributes to carcinogenesis. In this study, we set out to study the role of GATA6 expression on proliferation and apoptosis of pancreatic cancer cells and the role of reactive oxygen species.
METHODS: Four target miRNA sequences against GATA6 mRNA were synthesized and used to transfect SW1990 cells. Then, GATA6 expression in SW1990 cells was examined by western blot and quantative real-time polymerase chain reaction. Cell proliferation was examined by WST-8 and colony formation assay. Cell cycle progression and apoptosis were measured by flow cytometry. We also measured the generation of reactive oxygen species by immunofluorescence and flow cytometry.
RESULTS: RNA interference against GATA6 successfully inhibited mRNA and protein expression of GATA6 in the SW1990 pancreatic cancer cell line. Silencing of GATA6 by RNA interference inhibited cell proliferation and increased apoptosis of SW1990, and enhanced the expression of reactive oxygen species.
CONCLUSIONS: These results suggest that the RNA interference approach against GATA6 may be an effective therapeutic approach for treatment of pancreatic cancer.

Xiong CJ, Li PF, Song YL, et al.
Insulin induces C2C12 cell proliferation and apoptosis through regulation of cyclin D1 and BAD expression.
J Cell Biochem. 2013; 114(12):2708-17 [PubMed] Related Publications
Insulin is a secreted peptide hormone identified in human pancreas to promote glucose utilization. Insulin has been observed to induce cell proliferation and myogenesis in C2C12 cells. The precise mechanisms underlying the proliferation of C2C12 cells induced by insulin remain unclear. In this study, we observed for the first time that 10 nM insulin treatment promotes C2C12 cell proliferation. Additionally, 50 and 100 nM insulin treatment induces C2C12 cell apoptosis. By utilizing real-time PCR and Western blotting analysis, we found that the mRNA levels of cyclinD1 and BAD are induced upon 10 and 50 nM/100 nM insulin treatment, respectively. The similar results were observed in C2C12 cells expressing GATA-6 or PPARα. Our results identify for the first time the downstream targets of insulin, cyclin D1, and BAD, elucidate a new molecular mechanism of insulin in promoting cell proliferation and apoptosis.

Cheung WK, Zhao M, Liu Z, et al.
Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis.
Cancer Cell. 2013; 23(6):725-38 [PubMed] Free Access to Full Article Related Publications
Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype.

Tian F, Li D, Chen J, et al.
Aberrant expression of GATA binding protein 6 correlates with poor prognosis and promotes metastasis in cholangiocarcinoma.
Eur J Cancer. 2013; 49(7):1771-80 [PubMed] Related Publications
AIM: GATA6, a zinc-finger transcription factor, functions as a tumour promoter or suppresser according to different tumour origins. We investigated the clinical significance of GATA6 and its role in invasion and metastasis in cholangiocarcinoma (CCA).
METHODS: Expression of GATA6 in 87 cancerous, 24 paracancerous, 32 lymph-node metastatic and 8 liver metastatic samples from 87 CCA patients undergoing surgical resection was detected by immunohistochemistry. Impact of GATA6 on invasion, metastasis and 67kDa laminin receptor expression (67LR) was evaluated in CCA cells by shRNA lentivirus or expressed-plasmid transfection.
RESULTS: Aberrant expression of GATA6 in CCAs was significantly associated with lymph-node metastasis. GATA6 expression was higher in lymph-node and liver metastatic tissues compared with primary cancerous tissues. Kaplan-Meier analysis showed GATA6 expression correlated with poor overall survival and early recurrence in CCAs. Cox analysis suggested GATA6 was an independent prognostic marker for overall survival and recurrence-free survival. CCA cell invasion and migration were decreased by GATA6 knockdown and enhanced by GATA6 overexpression in vitro. Knockdown of GATA6 reduced CCA cell metastasis by xenotransplantation into nude mice. 67LR, which is overexpressed in CCAs and promotes invasion and metastasis through several pathways, positively correlated with GATA6 expression in 87 CCAs. Both mRNA and protein levels of 67LR were regulated by GATA6 in CCA cells. Moreover, ChIP analysis showed GATA6 bound to 67LR gene promoter in CCA cells.
CONCLUSION: Aberrant expression of GATA6 correlates with poor prognosis and promotes invasion and metastasis in CCA.

Skiriute D, Vaitkiene P, Saferis V, et al.
MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma.
BMC Cancer. 2012; 12:218 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Methylation of promoter region is the major mechanism affecting gene expression in tumors. Recent methylome studies of brain tumors revealed a list of new epigenetically modified genes. Our aim was to study promoter methylation of newly identified epigenetically silenced genes together with already known epigenetic markers and evaluate its separate and concomitant role in glioblastoma genesis and patient outcome.
METHODS: The methylation status of MGMT, CD81, GATA6, DR4, and CASP8 in 76 patients with primary glioblastomas was investigated. Methylation-specific PCR reaction was performed using bisulfite treated DNA. Evaluating glioblastoma patient survival time after operation, patient data and gene methylation effect on survival was estimated using survival analysis.
RESULTS: The overwhelming majority (97.3%) of tumors were methylated in at least one of five genes tested. In glioblastoma specimens gene methylation was observed as follows: MGMT in 51.3%, GATA6 in 68.4%, CD81 in 46.1%, DR4 in 41.3% and CASP8 in 56.8% of tumors. Methylation of MGMT was associated with younger patient age (p < 0.05), while CASP8 with older (p < 0.01). MGMT methylation was significantly more frequent event in patient group who survived longer than 36 months after operation (p < 0.05), while methylation of CASP8 was more frequent in patients who survived shorter than 36 months (p < 0.05). Cox regression analysis showed patient age, treatment, MGMT, GATA6 and CASP8 as independent predictors for glioblastoma patient outcome (p < 0.05). MGMT and GATA6 were independent predictors for patient survival in younger patients' group, while there were no significant associations observed in older patients' group when adjusted for therapy.
CONCLUSIONS: High methylation frequency of tested genes shows heterogeneity of glioblastoma epigenome and the importance of MGMT, GATA6 and CASP8 genes methylation in glioblastoma patient outcome.

Wang H, Liu Z, Li J, et al.
ΔNp63α mediates proliferation and apoptosis in human gastric cancer cells by the regulation of GATA-6.
Neoplasma. 2012; 59(4):416-23 [PubMed] Related Publications
The oncogenic isoform of the p63 protein, ΔNp63α, has been found to be overexpressed in numerous human squamous cell carcinomas. However, the role of ΔNp63α in human gastric cancer remains unknown. To evaluate this role, we screened a panel of gastric cancer cell lines for ΔNp63α expression and found that they are correlated with the differentiation status of the cell lines. Using the MKN28 gastric cancer cell line for loss-of-function or gain-of-function of ΔNp63α in our experiments, we observed that forced expression of ΔNp63α promoted cell proliferation as assessed by the MTT and colony formation assays, and increased the GATA-6 expression. In contrast, down-regulation of ΔNp63α via small interfering RNA suppressed cell proliferation, induced cell apoptosis, and reduced the expression of GATA-6. In conclusion, our data suggest that ΔNp63α plays an important role in cell growth and proliferation of gastric cancer cells, which may be associated with the regulation of GATA-6 expression. This is the first study exploring the biological functions and the underlying mechanism of ΔNp63α during gastric cancer development. It also identifies potential targets for anti-tumor treatment.

Mahoney SE, Yao Z, Keyes CC, et al.
Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas.
Epigenetics. 2012; 7(4):400-8 [PubMed] Free Access to Full Article Related Publications
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. While cytogenetic abnormalities have been well characterized in this disease, aberrant epigenetic events such as DNA hypermethylation have not been described in genome-wide studies. We have analyzed the methylation status of 25,500 promoters in normal skeletal muscle, and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. We identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Genes involved in tissue development, differentiation, and oncogenesis such as DNAJA4, HES5, IRX1, BMP8A, GATA4, GATA6, ALX3, and P4HTM were hypermethylated in both RMS cell lines and primary samples, implicating aberrant DNA methylation in the pathogenesis of rhabdomyosarcoma. Furthermore, cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.

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