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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: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
| PRJNA681605 | ENA
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:BackgroundThe loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Methodology/principal findingsHerein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Conclusions/significanceSince AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype.
| S-EPMC2929203 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-13 | GSE138711 | GEO
Project description:Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels reflect cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic, and predictive roles for CDR1as and expose circRNAs as key players in metastasis.
| S-EPMC7184928 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and lacks targeted therapies. Here, we reported a novel potential therapeutic target hematological and neurological expressed 1 like (HN1L) in HCC. First, HCC tissue microarray analysis showed that HN1L was frequently up-regulated in cancer tissues than that in normal liver tissues, which significantly associated with tumor size, local invasion, distant metastases, and poor prognosis for HCC patients. Functional studies demonstrated that ectopic expression of HN1L could increase cell growth, foci formation in monolayer culture, colony formation in soft agar and tumorigenesis in nude mice. In addition, HN1L could also promote HCC metastasis by inducing epithelial-mesenchymal transition. Inversely, silencing HN1L expression with shRNA could effectively attenuate its oncogenic function. We further showed that HN1L transcriptionally up-regulated methyltransferase like 13 (METTL13) gene in an AP-2γ dependent manner, which promoted cell proliferation and metastasis by up-regulating TCF3 and ZEB1. Importantly, administration of lentivirus-mediated shRNA interfering HN1L expression could inhibit tumorigenesis and metastasis in mice. Collectively, HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 promotes HCC growth and metastasis representing a promising therapeutic target in HCC treatment.
| S-EPMC6889153 | biostudies-literature