Rearranged ERG confers robustness to prostate cancer cells by subverting the function of p53.

Autor: Kaczorowski A; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Tolstov Y; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Falkenstein M; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Vasioukhin V; Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview, Avenue N C3-168, Seattle, 98109, Washington., Prigge ES; Department of Applied Tumor Biology, Institute of Pathology, University Hospital, Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Geisler C; Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Kippenberger M; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Nientiedt C; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Ratz L; Cancer Genome Research, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Kuryshev V; Cancer Genome Research, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Herpel E; Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany; Tissue Bank of the National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Kristiansen G; Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany., Sültmann H; Cancer Genome Research, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Stenzinger A; Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, D-69120, Heidelberg, Germany., Doeberitz MVK; Department of Applied Tumor Biology, Institute of Pathology, University Hospital, Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Hohenfellner M; Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Duensing A; Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany; Precision Oncology of Urological Malignancies, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, 15213, Pennsylvania; Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, 15213, Pennsylvania., Duensing S; Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Electronic address: stefan.duensing@med.uni-heidelberg.de.
Jazyk: angličtina
Zdroj: Urologic oncology [Urol Oncol] 2020 Sep; Vol. 38 (9), pp. 736.e1-736.e10. Date of Electronic Publication: 2020 Jul 13.
DOI: 10.1016/j.urolonc.2020.06.016
Abstrakt: Objective: ERG rearrangements are frequent and early events in prostate cancer. The functional role of rearranged ERG, however, is still incompletely understood. ERG rearrangements are maintained during prostate cancer progression suggesting that they may confer a selective advantage. The molecular basis of this notion is the subject of this study.
Methods: A variety of immunological methods were used to characterize the effects of rearranged ERG on p53. Consequences of an overexpression of N-terminally deleted ERG on p53 function were interrogated by measuring apoptosis and cellular senescence in the presence or absence of exogenous DNA damage. Effects of N-terminally deleted ERG on the transactivation function of p53 were analyzed by qRT-PCR.
Results: We show that overexpression of ERG leads to an increased basal level of DNA damage and a stabilization of p53 that involves a sequestration of its E3 ubiquitin ligase, MDM2, into nucleoli. A higher p53 expression was also observed in vivo in an ERG-overexpressing prostatic intraepithelial neoplasia mouse model. The correlation between ERG and p53 expression was corroborated in 163 patients with prostate cancer. ERG overexpression was found to inhibit both apoptosis and cellular senescence induced by exogenous DNA damage. Mechanistically, this protective effect of ERG involved an abrogation of the DNA damage-induced expression of p53 target genes.
Conclusions: By protecting tumor cells from the antiproliferative consequences of genotoxic stress, ERG may allow the survival and proliferation of genomically unstable tumor cells. Targeting ERG may therefore represent a promising strategy to suppress such adverse features during prostate cancer progression.
(Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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