Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA393996 | ENA |
REPOSITORIES: ENA
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Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.
2019-02-06 | GSE101323 | GEO
Project description:This study elucidates the effect of the E2F1-regulated melanoma-secreted factors on the phenotype and transcriptional program of immune cells (CD4+ T and CD8+ T cells) in the melanoma immune microenvironment. In order to determine the immune modulatory effect of the secretome on immune cells, we established a co-culture system where different melanoma cell lines (high-E2F1/invasive and low E2F1/non-invasive) were co-cultured with CD4+ or CD8+ T cells without direct interaction. These data describe the transcriptomes of immune cells and for the two melanoma cell lines Mel147 and C8161, both in co- and monoculture condition, with stable E2F1 knockdowns and corresponding controls.
2024-10-27 | E-MTAB-12750 | biostudies-arrayexpress
Project description:We demonstrate that the catalytic subunit of Polycomb Repressive Complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are co-expressed in GBM and significantly induced in post-irradiation recurrent tumors whose expression inversely correlated with patient prognosis. Through gain-and loss-of-function study, our data show that MELK or FOXM1 contributes on GSC radioresistance by regulation of EZH2. We used microarrays to validate EZH2 target gene expression. GSCs were treated with shNT (control), shMELK, shFOXM1, and EZH2 overexpression. Total RNA was isolated using the Qiagen RNeasy kit (Qiagen).
2015-04-16 | E-GEOD-63963 | biostudies-arrayexpress
Project description:The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers and therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS-mutants with bivalent H3K27me3 and Polycomb Repressive Complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1 and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS-mutants. Coincident with bivalent reprogramming the increased expression of pro-metastatic and melanocyte-specific cell identity genes are associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma, and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS-mutant melanoma patients.
2019-11-07 | GSE134043 | GEO
Project description:RNA-seq on NFATC2 knock-down (siRNA) on melanoma cell line A375
2017-09-29 | GSE99466 | GEO
Project description:The use of BRAF inhibitors, specific of the BRAFV600E mutation, as a therapeutic strategy for melanoma has significantly improved patient survival. However, resistance mechanisms appear systematically and limit the benefit of treatment. Here we show that AhR transcription factor participates in BRAFi resistance and is associated with the acquisition of an invasive and a dedifferentiated melanoma phenotype by controlling the expression of specific genes. AhR also induces the activation of the c-Src pathway through its phosphorylation, associated with BRAFi resistance. The use of a specific inhibitor of c-Src such as Dasatinib makes it possible to sensitize resistant cells to BRAFi and to prevent the acquisition of an invasive melanoma phenotype by regulating the expression of the AhR-dependent genes.
2022-10-18 | GSE166617 | GEO
Project description:We investigated the role of GATA2 in prostate cancer cells beyond the AR signaling axis, and characterized the pharmacological potency of the GATA2 small molecule inhibitor (SMI) K-11706 against prostate cancer cells. K-11706, which inhibited the proliferation and invasive behavior of PC cells, and dramatically reduced the genome-wide transcriptional activity of GATA2, AR, and cMyc, leading to downregulation of several prostate cancer drivers and AR/cMyc effector genes, notably FOXM1, EZH2, and CENPF. Transcriptional profiling and functional pathway analysis of the K-11706 transcriptomic footprint against curated databases delineated a biological network composed of genes involved in cell cycle/proliferation, stemness, metastasis and DNA repair.
2025-03-15 | GSE147173 | GEO
Project description:We investigated the role of GATA2 in prostate cancer cells beyond the AR signaling axis, and characterized the pharmacological potency of the GATA2 small molecule inhibitor (SMI) K-11706 against prostate cancer cells. K-11706, which inhibited the proliferation and invasive behavior of PC cells, and dramatically reduced the genome-wide transcriptional activity of GATA2, AR, and cMyc, leading to downregulation of several prostate cancer drivers and AR/cMyc effector genes, notably FOXM1, EZH2, and CENPF. Transcriptional profiling and functional pathway analysis of the K-11706 transcriptomic footprint against curated databases delineated a biological network composed of genes involved in cell cycle/proliferation, stemness, metastasis and DNA repair.
2025-03-15 | GSE147214 | GEO
Project description:We demonstrate that the catalytic subunit of Polycomb Repressive Complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are co-expressed in GBM and significantly induced in post-irradiation recurrent tumors whose expression inversely correlated with patient prognosis. Through gain-and loss-of-function study, our data show that MELK or FOXM1 contributes on GSC radioresistance by regulation of EZH2. We used microarrays to validate EZH2 target gene expression.
2015-04-16 | GSE63963 | GEO
Project description:PGC1-alpha is a transcriptional coactivator that controls diverse cellular processes, including metabolism. PGC1-alpha expression is increased in invasive primary melanoma. To understand the role of PGC1-alpha in the invasive growth of primary melanoma, we generated transcriptional (RNA-Seq) profiles of WM3248 primary melanoma cells that were transfected with either negative control or PGC1-alpha siRNA.
2020-02-12 | GSE145101 | GEO