EZH2 is a key component of Hepatoblastoma tumor cell growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA985457 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24967154_1.fastq.gz | Fastqsanger.gz | |||
| SRR24967154_2.fastq.gz | Fastqsanger.gz | |||
| SRR24967155_1.fastq.gz | Fastqsanger.gz | |||
| SRR24967155_2.fastq.gz | Fastqsanger.gz | |||
| SRR24967156_1.fastq.gz | Fastqsanger.gz |
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Project description:To understand molecular mechanisms driving HB pathogenesis, we hypothesize that pathologic activation of Enhancer of Zeste Homolog 2 contributes to hepatoblastoma propagation. Here we demonstrate that EZH2 promotes proliferation in HB cell lines through interaction with β-catenin, the most frequently mutated gene in HB. We demonstrate that canonical and noncanonical EZH2 signaling occur in HB tumor cells, likely driven by aberrant EZH2 expression. We use comparison groups of liver cancer, hepatocytes, and dermal fibroblasts to establish the hepatoblastoma identity of our patient-derived cell lines.
2023-11-15 | GSE235202 | GEO
Project description:BackgroundEnhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including β-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner.Methods and resultsWe demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with β-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and β-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.ConclusionsEZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.
| S-EPMC10842061 | biostudies-literature
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270769 | GEO
Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.
2025-05-01 | GSE270163 | GEO
Project description:Hepatoblastoma is a primary malignant liver tumor in children, thought to arise from abnormal liver development during the fetal period. Approximately 90% of cases harbor activating mutations in CTNNB1, which encodes β-catenin, while other genetic mutations are rare. Recent studies have shown that CTNNB1 mutations are frequently accompanied by increased expression of the transcriptional coactivator YAP, which promotes cell proliferation and suppresses apoptosis. Based on these findings, we established a hepatoblastoma model by introducing active forms of CTNNB1 and YAP into human iPSC-derived hepatoblasts. Cells transduced with both genes showed distinct morphological changes and upregulation of CTNNB1, YAP, and their downstream target genes. RNA-seq followed by Gene Set Enrichment Analysis (GSEA) revealed that the gene expression profile of these cells closely matches that of hepatoblastoma patients. Utilizing this model, we identified Prostate-Associated Gene 4 (PAGE4) as a novel candidate gene involved in hepatoblastoma progression. Functional analysis in hepatoblastoma cell lines (Huh6, HepG2) demonstrated that PAGE4 plays a role in promoting cell proliferation and resistance to apoptosis. Since PAGE4 is a known cancer/testis antigen with tumor-specific expression, it has been recognized as a potential target in cancer therapy. Our findings indicate that PAGE4 represents a novel and promising therapeutic target for hepatoblastoma.
2025-10-17 | GSE296904 | GEO
Project description:The mechanisms underlying hepatoblastoma are not well defined. To address this, we generated transcriptomic profiles of normal, background, and hepatoblastoma liver samples from patients aged 0.01 months to 6 years, using RNA-sequencing. Hepatoblasoma was histologically confirmed. Here we focus on the elevation of stem cell markers and the loss of tumor suppressor proteins leading to the development of hepatoblastoma in very young children.
2018-07-01 | GSE81928 | GEO
Project description:Hepatoblastoma (HB) is the most common primary liver malignancy of childhood. However, molecular investigations of the disease are limited and effective treatment options are lacking. The use of patient derived xenografts (PDX) to study biology and treatment strategies of HB has proven to be a useful tool. There is currently a knowledge gap in the investigation of key driver cells of HB in PDX models. Key driving pathways of HB tumor including WNT, AP-1, Hedgehog, Notch and MAPK pathways and genes such as GPC3, DLK1 and HMGA2 have been identified in primary HB tumor and PDX as integral players in HB tumor growth. Cell clusters have been defined with distinct roles in tumor development. Cell populations with initiating, angiogenic (endothelial), maintenance, and progression signatures have been identified in one HB patient tumor and corresponding PDX tumor. Critical pathways combined with identification of distinct cell populations within HB tumor will allow for investigation of novel treatment strategies in vitro and in vivo.
2021-07-29 | GSE180664 | GEO
Project description:Hepatoblastoma (HB) is the most common primary liver malignancy of childhood. However, molecular investigations of the disease are limited and effective treatment options are lacking. The use of patient derived xenografts (PDX) to study biology and treatment strategies of HB has proven to be a useful tool. There is currently a knowledge gap in the investigation of key driver cells of HB in PDX models. Key driving pathways of HB tumor including WNT, AP-1, Hedgehog, Notch and MAPK pathways and genes such as GPC3, DLK1 and HMGA2 have been identified in primary HB tumor and PDX as integral players in HB tumor growth. Cell clusters have been defined with distinct roles in tumor development. Cell populations with initiating, angiogenic (endothelial), maintenance, and progression signatures have been identified in one HB patient tumor and corresponding PDX tumor. Critical pathways combined with identification of distinct cell populations within HB tumor will allow for investigation of novel treatment strategies in vitro and in vivo.
2021-07-29 | GSE180665 | GEO