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

ABSTRACT: 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 PKCε 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43135 | GEO | 2012/12/28

SECONDARY ACCESSION(S): PRJNA184849

REPOSITORIES: GEO

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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

Transcriptionally inactive ATF2 variant drives melanomagenesis [Array]

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.

2016-05-02 | GSE81013 | GEO

Transcriptionally inactive ATF2 variant drives melanomagenesis [Seq]

2016-04-29 | GSE79917 | GEO

Expression profile of ATF2 knockdown in gastric cancer cell line MGC803 and genome-wide maps of ATF2 binding sites in gastric cancer cell line AGS [RNA-Seq]

Project description:Activation transcription factor 2 (ATF2), a member of the ATF/CREB family of transcription factors, is implicated in a broad spectrum of cancer-related biological functions, such as cell proliferation, apoptosis and DNA repair. Growing evidence indicates ATF2 act as an oncogene or a tumor suppressor in different cancer types depending on its expression level and subcellular localization. In this study, RNA-seq and ChIP-seq were performed for identification of genome-wide DNA binding sites and potential transcription targets for ATF2.

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Expression profile of ATF2 knockdown in gastric cancer cell line MGC803 and genome-wide maps of ATF2 binding sites in gastric cancer cell line AGS [ChIP-Seq]

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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

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

CHIP Analysis - c-Jun/ATF2

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

2004-10-06 | GSE1810 | GEO

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