Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma (ATAC-seq)

ABSTRACT: Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that this differentiated state is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the ACC epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205254 | GEO | 2023/04/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma (DNA methylation array)

Project description:Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that this differentiated state is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the ACC epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

2023-04-25 | GSE205272 | GEO

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma (RNA-seq)

2023-04-25 | GSE205261 | GEO

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma (ChIP-seq)

2023-04-25 | GSE205258 | GEO

Characterization of differential gene expression in adrenocortical tumors harbouring β-catenin (CTNNB1) mutations.

Project description:Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and carcinomas (ACC). However, the target genes of CTNNB1 have not yet been identified in adrenocortical tumors. Our objective was to identify genes de-regulated in adrenocortical tumors harbouring CTNNB1 genetic alterations.

2011-04-09 | GSE28476 | GEO

Characterization of differential gene expression in adrenocortical tumors harbouring β-catenin (CTNNB1) mutations.

2011-04-09 | E-GEOD-28476 | biostudies-arrayexpress

Impact of 5-azacytidine on DNA methylation and gene expression in ACC cell lines

Project description:Adrenocortical carcinomas (ACCs) are rare and aggressive endocrine cancers of the adrenal gland. Recently, a subtype of ACC characterized by a CpG island methylator phenotype (CIMP), associated with especially poor diagnosis, has been discovered. The purpose of this study is to investigate the role of DNA methylation and the impact on demethylating agent 5-azacytidine in ACC tumors aggressiveness. To this aim, we generated RRBS and RNAseq data from two ACC and one non-tumour cell lines treated or not with 5-azacytidine. We showed that CIMP has a direct impact on the aggressiveness of tumors through two main mechanisms; (1) by increasing survival and proliferation and (2) by favoring the tumor immune escape. These two mechanisms could at least partially be reversed upon 5-azacytidine treatment. Overall, our results show that strongly suggest that the co-treatment with demethylating agents to enhance the efficacy of immunotherapy could be beneficial for patients with high CIMP ACC.

2023-02-19 | GSE145560 | GEO

Identification of new TCF21 targets in adrenocortical carcinoma cells

Project description:Transcription factor 21 (TCF21) directly binds and regulates SF1 in tumor and normal adrenocortical cells, and both are involved in the development and steroidogenesis of the adrenal cortex. TCF21 is a tumor suppressor gene and its expression is reduced in malignant tumors. In adrenocortical tumors, it is less expressed in adrenocortical carcinomas (ACC) than in adrenocortical adenomas (ACA) and normal tissue. However, a comprehensive analysis to identify TCF21 targets have not yet been conducted in any type of cancer. In this study, we performed Chromatin Immunoprecipitation and Sequencing (ChIP-Seq) in adrenocortical carcinoma cell line (NCI-H295R) overexpressing TCF21, with the aim of identifying TCF21 new targets. The five most frequently identified sequences corresponded to the PRDM7, CNTNAP2, CACNA1B, PTPRN2 and KCNE1B genes. Validation experiments showed that, in NCI-H295R cells, TCF21 regulates gene expression positively in PRDM7 and negatively in CACNA1B. Recently, it was observed that the N-type calcium channel v2.2 (Cav2.2) encoded by CACNA1B gene is important in Angiotensin II signal transduction for corticosteroid biosynthesis in NCI-H295R adrenocortical carcinoma cells. Indeed, TCF21 inhibits CACNA1B and Cav2.2 expression in NCI-H295R. In addition, in a cohort of 55 adult patients with adrenocortical tumor, CACNA1B expression was higher in ACC than ACA, and was related to poor disease-free survival in ACC patients. These results suggest a mechanism of steroidogenesis control by TCF21 in adrenocortical tumor cells, in addition to the control observed through SF1 inhibition. Importantly, steroid production could impair tumor immunogenicity, contributing to the immune resistance described in adrenal cancer.

2022-06-30 | GSE179308 | GEO

RNA-sequencing and ChIP-sequencing in murine mesenchymal stem cells treated with Ezh2 inhibitor GSK126 or β-catenin siRNA

Project description:During mesenchymal stem cell (MSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin is thought to play a critical role in Wnt effects. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chip-seq showed that β-catenin associated with the promoter of EZH2, a key component of the PRC2 complex that governs genome methylation. Knocking down β-catenin lowered EZH2 levels and H3K27me3 at osteogenic loci. Further, when EZH2 was inhibited, β-catenin ’s anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin effects on MSC to preserve MSC multipotentiality.

2019-10-17 | GSE138980 | GEO

FSCN1 as a new druggable target in adrenocortical carcinoma

Project description:Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatisation. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with the Rho/Rac GEF VAV2 in enhancing the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here we showed that FSCN1 is a transcriptional target for Beta-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. Additionally, FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When SF-1 dosage was upregulated in H95R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of ACC cell lines (CU-ACC2, JIL-2266, MUC-1) expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 represents a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC, possibly in combination with immunotherapy.

2023-03-20 | MTBLS6402 | MetaboLights

Beta-catenin status effects in human adrenocortical carcinomas (33), adenomas (22), and normal adrenal cortex (10)

Project description:We scored adrenocortical carcinomas and adenomas for abnormal beta-catenin staining, and sequenced the beta-catenin gene in some samples. We compared adrenocortincal carcinomas with and without abnormal beta-catenin staining and found many significant expression differences and significant results from enrichment testing. A similar comparison in the adenomas gave relatively few differences, and they did not correlate to differences found for the carcinomas. Abnormal beta-catenin staining was associated with mitotic rate and poorer patient survival in the carcinomas. In a second independent data set (given in a supplement) we again found beta-catenin associated with poor survival. The array data given is the same as GEO series GSE10927, with additional characteristics about beta-catenin, and new patient followup data. The analysis shown in a supplementary Excel file is also new. Human samples of 33 adrenocortical carcinomas, 22 adrenocortical adenomas, and 10 normal adrenal cortex samples, each from a different patient, had mRNA assays performed using Affymetrix HG_U133_plus_2 arrays, with 54675 probe-sets. 23 of the carcinomas were used in survival analysis. 27 additional samples without array data were also used in a survival analysis.

2011-11-02 | E-GEOD-33371 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data