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β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens Drosophila melanogaster

PROVIDER: GSE205283 | GEO | 2023/04/25

REPOSITORIES: GEO

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

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 | GSE205261 | GEO

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

2023-04-25 | GSE205258 | GEO

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

2023-04-25 | GSE205254 | GEO

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

2023-04-25 | GSE205272 | GEO

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

Project description:β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

| PRJNA844312 | ENA

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

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

| PRJNA844287 | ENA

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

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

| PRJNA844295 | ENA

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

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

| PRJNA844297 | ENA

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

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

| PRJNA844307 | ENA

Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice.

Project description:Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS)Cre mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.

| S-EPMC7378041 | biostudies-literature

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