Oncogenic roles of SETDB2 histone methyltransferase in gastric cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76135 | GEO | 2016/02/21
SECONDARY ACCESSION(S): PRJNA306413
REPOSITORIES: GEO
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Project description:Histone H3 lysine 9 tri-methyltransferases (H3K9me3) are related to transcriptional gene silencing. Although SETDB2 has H3K9me3 activity, it is unknown whether SETDB2 is linking to carcinogenesis. Here, we studied alterations and functions of SETDB2 in gastric cancers (GCs). In human clinical samples, overexpression of SETDB2 protein was observed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts, and significantly associated with poor prognosis of the patients (P<0.05). SETDB2 protein was significantly detected in late stage of GCs. Moreover, SETDB2 protein was strongly expressed in four (30.8%) of 13 GC cell lines, and knockdown of SETDB2 led to decrease the cell proliferation, migration and invasion. According to the microarray analysis on a GC cell line after knockdown of SETDB2, the expression of WWOX and CADM1 tumor suppressor genes was significantly up-regulated. ChIP analysis showed that the H3K9me3 levels at the promoter regions of WWOX and CADM1 genes were closely regulated by the SETDB2 in GC cells. We also found that SETDB2 bound to the promoter regions after SETDB2 overexpression. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, through H3K9me3, and hence overexpression of SETDB2 may contribute to gastric progression. Transfection of SETDB2 siRNA into MKN74 cells were performed by electroporation. After 48hrs, cells were harvested. Total RNA was used for cDNA microarray.
2016-02-21 | E-GEOD-76135 | biostudies-arrayexpress
Project description:As the primary driving forces of gastrulation, convergence and extension (C&E) movements lead to a medio-lateral narrowing and an anterior-posterior elongation of the embryonic body axis. Histone methylation as a post-translational modification plays a critical role for early embryonic development, but its functions on C&E movements remaine largely unknown. Here, we uncover that knockdown of setdb2, a SET domain-containing protein possessing potential histone H3K9 methyltransferase activity, induces abnormal C&E movements. Then, we perform genome-wide gene expression profiling of zebrafish in 6h control embryos and setdb2 morphant embryos to address the downstream target of setdb2 gene.
2014-06-20 | E-MTAB-2207 | biostudies-arrayexpress
Project description:Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality necessitating further improvements in diagnosis and therapy. Targeted therapies directed against epigenetic regulators, which are frequently mutated or misregulated in acute leukemia, are emerging as candidate approaches in preclinical studies and early trials. However, the epigenetic factors involved in most ALLs are not well defined or functionally characterized. In this study, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is over-expressed in a wide spectrum of leukemias, required for their maintenance in vitro and in vivo, and its elevated expression correlates with a poor prognosis in clinical cohorts. In a subset of ALL with the preBCR+ phenotype, SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1. In this subset, SETDB2 epigenetically suppresses expression of the cell cycle inhibitor CDKN2C through histone H3K9 tri-methylation thus establishing a novel oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. In addition to targeting SETDB2 alone, its knockdown significantly enhanced sensitivity to kinase and epigenetic inhibitors suggesting a potential approach to future combination treatments. Our studies define an epigenetic role for SETDB2 in leukemia pathogenesis, and provide a mechanistic rationale for targeting SETDB2 therapeutically in a subset of leukemia.
2018-05-30 | GSE102947 | GEO
Project description:Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified the histone methyltransferase, SETDB2, in macrophages drives tissue repair by repressing NFκB-mediated inflammation. Complementary ATAC and RNA sequencing of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NFkB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages yet, paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NFKB component, RELA, leading to increased RELA/NFKB-mediated inflammatory gene expression. Further, RNA sequencing in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally co-regulate overlapping genes. Finally, in diabetic wound macrophages STAT3 expression and STAT3-SETDB2 binding were increased. As such, we identify what we believe to be a novel SETDB2-STAT3 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.
2024-11-06 | GSE274112 | GEO
Project description:Background and Aims: Gastric adenocarcinoma (gastric cancer, GC) is a major cause of global cancer mortality. Identifying molecular programs contributing to GC patient survival may improve our understanding of GC pathogenesis, highlight new prognostic factors, and reveal novel therapeutic targets. We aimed to produce a comprehensive inventory of gene expression programs expressed in primary GCs, and to identify those expression programs significantly associated with patient survival. Methods: Using a network modeling approach, we performed a large scale meta-analysis of GC transcriptome data integrating 940 gastric transcriptomes from multiple independent patient cohorts. We analyzed a training set of 428 GCs and 163 non neoplastic gastric mucosa (‘non-malignants’), and a validation set of 288 GCs and 61 non-malignants. Results: We identified 178 gene expression programs (modules) expressed in primary GCs, which were associated with distinct biological processes, chromosomal location patterns, cis-regulatory motifs, and clinicopathological parameters. Amongst these modules, expression of a TGF-B-signaling associated “super-module” of stroma-related genes consistently predicted patient survival in multiple GC validation cohorts. Analysis of histopathological tissue sections from gastrectomy specimens revealed that expression of this stromal module was associated with the proportion of intra-tumoral stroma (ITS). Further supporting the stromal module expression/ITS association, we found that the ITS proportion, measured directly from tissue sections, also predicted GC patient survival. Conclusion: Stromal gene expression predicts GC patient survival in multiple independent cohorts and may be closely related to the ITS proportion, a specific morphological GC phenotype. These findings suggest that therapeutic approaches targeting pathways associated with the GC stroma may merit evaluation.
2012-07-05 | GSE37023 | GEO
Project description:Epigenetic modifications of the genome, including DNA methylation, histone methylation/acetylation and noncoding RNAs, have been reported to play a fundamental role in regulating immune response during the progression of atherosclerosis. SETDB2 is a member of the KMT1 family of lysine methyltransferases and members of this family typically methylate histone H3 Lys9 (H3K9), an epigenetic mark associated with gene silencing and previous studies have shown SETDB2 is involved in innate and adaptive immunity, the pro-inflammatory response and hepatic lipid metabolism. Here we report that the expression of SETDB2 is markedly upregulated in human and murine atherosclerotic lesions. The upregulation of SETDB2 is observed in pro-inflammatory M1, but not anti-inflammatory M2 macrophages (MΦ). Notably, we found that genetic deletion of SETDB2 in hematopoietic cells promotes vascular inflammation and enhances the progression of atherosclerosis in bone marrow transfer studies in LDLR knockout mice. Single cell RNA-Seq analysis in isolated CD45+ cells from atherosclerotic plaques from mice with SETDB2 deficient bone marrow revealed a significant increase in inflammatory macrophage population and enhanced expression of genes involved in inflammation, myeloid cell recruitment and lipid metabolism. Additionally, we found that loss of SETDB2 in hematopoietic cells is associated with macrophage accumulation in atherosclerotic lesions, macrophage proliferation and attenuated efferocytosis. Overall, these studies identify SETDB2 as an important inflammatory cell regulator that controls macrophage activation in atherosclerotic plaques.
2021-03-18 | GSE169112 | GEO
Project description:A large-scale characterization of the methylation states of candidate CpG islands (CGIs) throughout the gastric cancer methylome has not previously been conducted. Genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic gastric carcinomas (GCs) and their surgical margins (SMs). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. Differential methylation was observed in CGIs near transcription start sites of 546 genes between GCs and SMs, and 601 genes between metastatic and non-metastatic GCs. From the list of differentially methylated CGIs, 68 candidate genes and 10 known tumor-related genes were selected for further characterization based on their known molecular function using DHPLC. Significant differential methylation was validated in the CGIs of 15 genes between GCs and SMs (Ps<0.05) and confirmed using bisulfite-sequencing. These genes include BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypomethylation of CGIs correlated with up-regulation of GFRA1 expression in GCs, while hypermethylation of other genes inactivated their transcription. Most importantly, prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients’ overall survival throughout discovery and testing cohorts in China as well as independent validation cohorts in Japan and Korea. In conclusion, methylation changes in the CGIs of 15 genes correlated strongly with GC development. GFRA1 hypomethylation and SRF and ZNF382 hypermethylation are potential synergistic biomarkers for the prediction of GC metastasis. To identify differential methylation of CGIs related to GC development and metastasis, genome-wide DNA methylation changes in 8 pairs of GC and SM samples were analysed using the MCAM assay with a 99K custom-designed Agilent oligonucleotide microarray composed of 99,027 probes targeting 6,177 unique protein-coding genes containing at least two methylation-sensitive/insensitive SmaI/ XmaI restriction sites (CCC|GGG/ C|CmCGGG) as described in Shen et al, PLoS Genet 3, 2023-2036 (2007).
2014-06-02 | E-GEOD-47724 | biostudies-arrayexpress
Project description:Epithelial-mesenchymal transition (EMT) is in the highlights as a significant role in tumor progression and invasion. Snail was known as the one of regulators of EMT in various malignant tumors. The aim of this study was to investigate the effect of Snail on invasiveness/migratory ability of gastric cancer cell lines and clinicopathological and prognostic significance of Snail over-expression using immunohistochemistry in tissue microarray of 314 gastric adenocarcinomas (GC). Differential gene expression in Snail over-expressed GC was investigated using cDNA microarray analysis. Silencing of Snail by ShRNA induced decreased of invasion, migration of gastric cancer cell lines. In contrast, over-expression of Snail induced increased invasiveness and migratory ability of gastric cancer cell lines in accordance increase of VEGF and MMP11. Furthermore, the over-expression of Snail (?75% nuclear staining of Snail) was significantly associated with tumor progression (p<0.0001), lymph node metastases (p=0.002), lymphovascular invasion (p=0.002), and perineural invasion (p=0.002) in 314 GC patient. Snail over-expression was also associated with poor prognosis (shorter survival) in GC patients (p=0.023). cDNA microarray revealed 213 differential expressed genes in Snail over-expressed GC tissues, including genes related to metastasis, invasion. Based on above results, it was suggested that Snail plays a significant role in invasiveness/migratory ability of GCs. In addition, Snail might be used to predictive biomarker for evaluation of prognosis or aggressiveness in GCs. 48 primary gastric adenocarcinoma fresh frozen tissues were used for microarray. All the tissues were obtained after curative resection after pathologic confirm at Pusan National University Hospital (PNUH, Busan, Korea) and Cheonnam University Hospital (CNUH, Cheonnam, Korea). Microarray experiment and data analysis were done at Cancer research institute, PNUH, Busan, Korea.
2012-05-17 | E-GEOD-38024 | biostudies-arrayexpress
Project description:Background & Aims: E-cadherin expression disruption is commonly observed in epithelial cancers and metastasis. Such event is also recognized as a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression and function of pivotal cancer-related genes, we characterized and dissected a pathway initiated by loss of microRNA-101 that causes E-cadherin dysfunction through upregulation of EZH2 expression in GC. Methods: Microarrays were used to profile the expression of microRNAs in human GC. Array-CGH revealed DNA copy number changes that were validated by genomic quantitative PCR and Snapshot. Expression levels of microRNAs, mRNA and protein were determined by quantitative-real time PCR and western-blot/co-immunofluorescence. CDH1 inactivating mechanisms were analyzed. Gain and loss of function experiments were done in KatoIII cells. E-cadherin functionality was assessed by immunofluorescence and flow cytometry. Results: MiR-101 expression was significantly decreased in tumors in comparison with normal gastric mucosas (P<.0001). In 65% of the analyzed GC cases, miR-101 downregulation was caused by deletions and/or microdeletions at miR-101-2 locus. EZH2 overexpression and consequent loss/aberrant E-cadherin expression was found in concomitance with miR-101 downregulation in 41% of the analyzed GC cases. This occurred preferentially in cases retaining allele(s) untargeted by classical CDH1 inactivating mechanisms. MiR-101 gain of function experiments or direct inhibition of EZH2, led to a strong depletion of endogenous EZH2 protein and consequent rescue of functional E-cadherin at the cell membrane, mimicking results obtained with clinical GC samples. Conclusions: Deletions and/or microdeletions at miR-101-2 locus underlying mature miR-101 downregulation and consequent EZH2 overexpression represented a novel cascade of genetic events leading to E-cadherin disruption, preferentially affecting the intestinal-type of GC. In the present study, 37 primary GCs and a pool of 10 normal gastric mucosas were used to acquire the expression of 703 known human mature miRNAs deposited in the Sanger miRBase Sequence Database, Release 10.0 (http://microrna.sanger.ac.uk), as well as 393 novel human miRNAs discovered through deep sequencing and validated by qRT-PCR and array profiling (NCodeM-bM-^DM-" Human miRNA microarray probe set V3 from Invitrogen). The 10 normal gastric mucosa RNA samples were pooled to obtain the normal gastric reference sample, which was labelled and hybridised four times to check arrays' reproducibility.
2012-07-31 | E-GEOD-33743 | biostudies-arrayexpress
Project description:Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.
2018-08-14 | GSE112369 | GEO