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The activating transcription factor 2: an influencer of cancer progression.

ABSTRACT: In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated 'cancer gene chameleon' ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.

SUBMITTER: Huebner K

PROVIDER: S-EPMC6923166 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Project description:In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4-0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

Project description:Epstein-Barr virus (EBV) is associated with particular forms of gastric cancer (GC). We previously showed that EBV infection into gastric epithelial cells induced aberrant DNA hypermethylation in promoter regions and silencing of tumor suppressor genes. We here undertook integrated analyses of transcriptome and epigenome alteration during EBV infection in gastric cells, to investigate activation of enhancer regions and related transcription factors (TFs) that could contribute to tumorigenesis. Formaldehyde-assisted isolation of regulatory elements (FAIRE) sequencing (-seq) data revealed 19 992 open chromatin regions in putative H3K4me1+ H3K4me3- enhancers in EBV-infected MKN7 cells (MKN7_EB), with 10 260 regions showing increase of H3K27ac. Motif analysis showed candidate TFs, eg activating transcription factor 3 (ATF3), to possibly bind to these activated enhancers. ATF3 was considerably upregulated in MKN7_EB due to EBV factors including EBV-determined nuclear antigen 1 (EBNA1), EBV-encoded RNA 1, and latent membrane protein 2A. Expression of mutant EBNA1 decreased copy number of the EBV genome, resulting in relative downregulation of ATF3 expression. Epstein-Barr virus was also infected into normal gastric epithelial cells, GES1, confirming upregulation of ATF3. Chromatin immunoprecipitation-seq analysis on ATF3 binding sites and RNA-seq analysis on ATF3 knocked-down MKN7_EB revealed 96 genes targeted by ATF3-activating enhancers, which are related with cancer hallmarks, eg evading growth suppressors. These 96 ATF3 target genes were significantly upregulated in MKN7_EB compared with MKN7 and significantly downregulated when ATF3 was knocked down in EBV-positive GC cells SNU719 and NCC24. Knockdown of ATF3 in EBV-infected MKN7, SNU719, and NCC24 cells all led to significant decrease of cellular growth through an increase of apoptotic cells. These indicate that enhancer activation though ATF3 might contribute to tumorigenesis of EBV-positive GC.

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The activating transcription factor 2: an influencer of cancer progression.

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