AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis
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ABSTRACT:
PROVIDER: PRJNA681605 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13169522.fastq.gz | Fastqsanger.gz | |||
| SRR13169523.fastq.gz | Fastqsanger.gz | |||
| SRR13169524.fastq.gz | Fastqsanger.gz | |||
| SRR13169525.fastq.gz | Fastqsanger.gz | |||
| SRR13169526.fastq.gz | Fastqsanger.gz |
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Project description:In melanoma metastasis, the role of the AP-2alpha transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2alpha interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2alpha removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment witj tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable anti-metastatic effects, which were dependent on AP-2alpha. Single cell RNA-seq analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2aHigh/E2F activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2alpha/EZH2 pathway and suggest that AP-2alpha expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas.
2021-06-29 | GSE162363 | GEO
Project description:In melanoma metastasis, the role of the AP-2alpha transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2alpha interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2alpha removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment witj tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable anti-metastatic effects, which were dependent on AP-2alpha. Single cell RNA-seq analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2aHigh/E2F activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2alpha/EZH2 pathway and suggest that AP-2alpha expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas.
2021-06-29 | GSE162362 | GEO
Project description:AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis [RNA-seq]
| PRJNA681604 | ENA
Project description:AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis [ChIP-seq]
| PRJNA681607 | ENA
Project description:In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2a High/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.
| S-EPMC8416798 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-06-29 | GSE162364 | GEO
Project description:Bladder cancer (BC) is a highly prevalent human disease in which Rb pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. Whole transcriptional characterizations of the mouse bladder tumors revealed a significant overlap with human BC samples, and a predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, we determined that in human superficial BC patients, the increased tumor recurrence and progression in these recurrences is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development. Gene expression was analyzed in normal bladder and bladder tumours, both in humans and in transgenic mice.
2014-10-02 | E-GEOD-38264 | biostudies-arrayexpress
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:Bladder cancer (BC) is a highly prevalent human disease in which Rb pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. Whole transcriptional characterizations of the mouse bladder tumors revealed a significant overlap with human BC samples, and a predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, we determined that in human superficial BC patients, the increased tumor recurrence and progression in these recurrences is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.
2014-10-02 | GSE38264 | GEO
Project description:Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumourigenesis in vivo remains poor, in particular in metastasising solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical Ezh2 inhibitor GSK503 stabilises the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress melanoma growth and prevent EMT / metastasis in vivo revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanomagenesis, which makes EZH2 a promising target for novel melanoma therapies.
2014-11-12 | GSE63165 | GEO