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      ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling


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          We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/ cyclin-A2/ cyclin-D1/ JUN/ MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

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          Most cited references26

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            Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.
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              Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.

              Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                December 2018
                09 November 2018
                : 7
                : 12
                : 1397-1408
                [1 ]Department of Pathology & Laboratory Medicine , University of Rochester Medical Center, Rochester, New York, USA
                [2 ]James P. Wilmot Cancer Institute , University of Rochester Medical Center, Rochester, New York, USA
                [3 ]Department of Pathology , Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [4 ]James Buchanan Brady Urological Institute , Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [5 ]Department of Pathology , University of Alabama at Birmingham, Birmingham, Alabama, USA
                [6 ]Department of Urology , University of Rochester Medical Center, Rochester, New York, USA
                Author notes
                Correspondence should be addressed to H Miyamoto: hiroshi_miyamoto@ 123456urmc.rochester.edu
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                : 19 October 2018
                : 09 November 2018

                androgen receptor,atf2,erk,neoplastic transformation,prognosticator,tumor progression,urothelial cancer


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