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CpG Hypermethylation and WNT/AP-1 cooperativity Define the Epigenetic Landscape and a Clinical Subgroup of High-Risk Pediatric Adrenocortical Carcinoma [Methylation array]

ABSTRACT: Treatment of three adult ACC cell lines (H295R and ACC1, ACC2) with entinostat and decitbaine led to consistent dose-dependent changes in DNA methylation patterns. These findings support entinostat's potential to reverse high-risk epigenetic programs in pACT and highlight HDAC inhibition as a promising therapeutic avenue, particularly when combined with established treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336709 | GEO | 2026/08/12

REPOSITORIES: GEO

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CpG Hypermethylation and WNT/AP-1 cooperativity Define the Epigenetic Landscape and a Clinical Subgroup of High-Risk Pediatric Adrenocortical Carcinoma [cell line]

Project description:Treatment of two adult ACC cell lines (H295R and CU-ACC1) with the HDAC inhibitor entinostat led to consistent dose-dependent reductions in viability, outperforming the DNA demethylating agent decitabine. scRNA-seq analyses revealed global transcriptional reprogramming. This included downregulation of AP-1 transcription factors (FOS, JUND, JUNB), suppression of oxidative phosphorylation and steroidogenic pathways, and increased expression of pro-apoptotic genes. These findings support entinostat's potential to reverse high-risk epigenetic programs in pACT and highlight HDAC inhibition as a promising therapeutic avenue, particularly when combined with established treatments.

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CpG Hypermethylation and WNT/AP-1 cooperativity Define the Epigenetic Landscape and a Clinical Subgroup of High-Risk Pediatric Adrenocortical Carcinoma

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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.

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CpG Hypermethylation and WNT/AP-1 cooperativity Define the Epigenetic Landscape and a Clinical Subgroup of High-Risk Pediatric Adrenocortical Carcinoma [methylation array]

2026-08-12 | GSE308221 | GEO

Identification of new TCF21 targets in adrenocortical carcinoma cells

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Project description:Background: Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data prognostic biomarkers and novel therapeutic targets. Methods: 44 ACC and 4 normal adrenal glands were profiled on Affymetrix U133 Plus 2 expression microarrays and pathway and transcriptional enrichment analysis performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed as validation data sets. Results: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). These findings were confirmed by our analysis of previously published datasets. Treatment of ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively). Conclusion: Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.

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2025-07-21 | GSE261006 | GEO

Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma

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Project description:The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive adrenocortical carcinoma (ACC) and represents a reliable prognostic indicator. We investigated the effects of FSCN1 inactivation by CRISPR/Cas9 in ACC H295R cells on global gene expression profiles in those cells. We performed gene expression profiling analysis using data obtained from RNA-seq of 2 different H295R control clones and 2 different FSCN1 KO clones (2 biological replicates for each clone).

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