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Transcriptionally inactive ATF2 variant drives melanomagenesis [Array]

ABSTRACT: Characterized by striking metastatic propensity and chemoresistance, melanoma is among the most lethal cutaneous malignancies. The transcription factor ATF2 was shown to elicit oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, a mouse model engineered to express a transcriptionally inactive form of Atf2 (Atf2?8,9) was found to be sufficient to induce nevi formation and, when crossed with BrafV600E animals, to promote melanoma development. The cross of Atf2?8,9 with BrafV600E;Pten-/- mice augmented pigmentation, tumorigenicity, and metastasis. Similar to mouse Atf2?8,9, the human ATF2 splice variant 5 enhanced growth and migration capacity of cultured melanoma and immortalized melanocytes. Induced Melan-A, CXCL9, S100A8, CCR7 expression, seen in Atf2?8,9-driven tumors associate with their enhanced pigmentation, immune infiltration and propensity to metastasize. Notably, elevated ATF2SV5 expression in melanoma specimens coincided with poor prognosis. The gain-of-function activity elicited by the truncated ATF2 form offers unexpected insight into mechanisms underlying melanoma development and progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE81013 | GEO | 2016/05/02

SECONDARY ACCESSION(S): PRJNA320281

REPOSITORIES: GEO

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Transcriptionally inactive ATF2 variant drives melanomagenesis [Seq]

Project description:Characterized by striking metastatic propensity and chemoresistance, melanoma is among the most lethal cutaneous malignancies. The transcription factor ATF2 was shown to elicit oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, a mouse model engineered to express a transcriptionally inactive form of Atf2 (Atf2?8,9) was found to be sufficient to induce nevi formation and, when crossed with BrafV600E animals, to promote melanoma development. The cross of Atf2?8,9 with BrafV600E;Pten-/- mice augmented pigmentation, tumorigenicity, and metastasis. Similar to mouse Atf2?8,9, the human ATF2 splice variant 5 enhanced growth and migration capacity of cultured melanoma and immortalized melanocytes. Induced Melan-A, CXCL9, S100A8, CCR7 expression, seen in Atf2?8,9-driven tumors associate with their enhanced pigmentation, immune infiltration and propensity to metastasize. Notably, elevated ATF2SV5 expression in melanoma specimens coincided with poor prognosis. The gain-of-function activity elicited by the truncated ATF2 form offers unexpected insight into mechanisms underlying melanoma development and progression.

2016-04-29 | GSE79917 | GEO

Inhibition of Melanoma Growth by Small Molecules that Promote the Mitochondrial Localization of ATF2

2012-12-28 | GSE43135 | GEO

NRG1/ERBB3 signaling in melanocyte Melan-Ink4a cells

Project description:Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. Gene expression changes are compared between Melan-Ink4a cells stimulated with NRG1-b1 (NRG1) for 21 days and NRG1 untreated Melan-INK4a cells in triplicate using Affymetrix Mouse GeneChip 1.0 ST chip .

2010-05-07 | E-GEOD-21463 | biostudies-arrayexpress

Inhibition of Melanoma Growth by Small Molecules that Promote the Mitochondrial Localization of ATF2

Project description:Effective therapy for malignant melanoma, the leading cause of death from skin cancer, remains an area of significant unmet need in oncology. Increased expression of PKC? in advanced metastatic melanoma, results in the phosphorylation of the transcription factor ATF2 on threonine 52, which causes its nuclear localization and confers its oncogenic activities. The nuclear-to-mitochondrial translocation of ATF2 following genotoxic stress promotes apoptosis, a function that is largely lost in melanoma cells, due to its confined nuclear localization. Therefore, promoting the nuclear export of ATF2, which sensitizes melanoma cells to apoptosis, offers a novel therapeutic modality. We conducted a pilot high-throughput screen of 3,800 compounds to identify small molecules that promote melanoma cell death by inducing the cytoplasmic localization of ATF2. For this specific gene expression analysis experiment, we subjected WM793 melanoma cells to treatment with DMSO- or 10µM SBI-0087702 for 24 h. RNA was harvested and subjected to microarray analyses using the Illumina Human HT-12 v4 BeadChip. Raw microarray data were normalized using the lumi package in R (variant stabilizing transformation followed by quantile normalization). Subsequent variant-stabilized, normalized microarray values were sorted by fold-change values and subjected to a 1.5-fold-change cut-off threshold. The fold-change-ranked gene list was subjected to gene ontological enriched functional network clustering using the Ingenuity (IPA) gene ontology platform.

2012-12-28 | E-GEOD-43135 | biostudies-arrayexpress

miR-193b represses cell proliferation and regulates cyclin D1 in melanoma: benign nevi and metastatic melanoma

Project description:Cutaneous melanoma is an increasingly common form of skin cancer. The molecular mechanisms regulating melanoma progression are not completely understood. We speculated that specific miRNAs may be involved in melanoma development. We compared the miRNA expression profiles of benign nevi and metastatic melanomas. Unsupervised hierarchical clustering demonstrated a distinct miRNA expression pattern in metastatic melanomas compared to nevi. We identified miRNAs that were differentially expressed in melanoma. Notably, miR-193b was significantly down-regulated in the melanoma tissue examined. Using functional studies we demonstrated that over-expression of miR-193b significantly reduced melanoma cell proliferation, and arrested cell at G1 phase. Further gene expression analysis revealed that miR-193b regulated targets involved in cell cycle. Cyclin D1 was down-regulated by miR-193b at both the mRNA and protein level. This is the first study to show that the miR-193b may reduce cell proliferation by directly repressing cyclin D1. Overall, our study suggests that miRNAs are dysregulated in metastatic melanoma, and that miR-193b may play an important role in melanoma. 8 benign nevi and 8 metastatic melanoma tissue samples were profiled by Agilent MicroRNA Microarray (V1.5).

2010-05-16 | E-GEOD-18509 | biostudies-arrayexpress

Identification of ATF2 target genes

Project description:In order to identify transcriptional targets of ATF2, we used a recombinant adenovirus to express constitutively active ATF2 in murine hepatoblasts. Expression of GFP was the control condition. Total RNA was harvested from cells 8 hours post infection. Reverse transcription was performed using Ovation Pico WTA kit (NuGen, 3300-12). Labelling, Encore Biotin Module (NuGen, 4200-12) three replicates GFP control and C2ATF2

2013-11-10 | E-GEOD-50530 | biostudies-arrayexpress

Identification of ATF2 target genes

2013-11-10 | GSE50530 | GEO

RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas

Project description:Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-Seq analysis of laser-microdissected melanocytic nevi (n=23) and primary melanoma samples (n=57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbour signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbour signatures of anti-PD-1 antibody treatment resistance. Transcriptomic signatures suggest that the epigenetic regulators SMARCA2 and SMARCA4 are differentially involved in the epigenetic programming of the two melanoma types. Pseudotime dynamics of nevus and melanoma samples reflect a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy.

2018-07-19 | GSE112509 | GEO

CHIP Analysis - c-Jun/ATF2

Project description:Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress

2010-06-05 | E-GEOD-1810 | biostudies-arrayexpress

Myometrial cells expressing CREB, CREM alpha, CREM tau2alpha, ATF2 or the ATF2-small gene

Project description:Human myometrial cells taken from biopsies of pre-menopausal non-cancerous non-pregnant uteri were cultured in complete MEM D-valine medium plus 10% FCS, and stably-transfected with the pcDNA3.1/V5-His TOPO vector (Invitrogen) harbouring either CREB, CREM alpha, CREM tau2alpha, ATF2, ATF2-small gene or a control empty-vector. Total RNA was extracted using TRI-reagent (Sigma) and RNeasy columns (Qiagen), and 10 ug used in target preparation for array hybridization. Keywords: other

2004-02-21 | GSE1059 | GEO

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