Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis.

Autor:	Welz L; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Kakavand N; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Hang X; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Laue G; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Ito G; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan., Silva MG; Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany., Plattner C; Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria., Mishra N; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Tengen F; Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany., Ogris C; Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany., Jesinghaus M; Institute of Pathology, University Hospital Marburg, Marburg, Germany., Wottawa F; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Arnold P; Institute of Functional and Clinical Anatomy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany., Kaikkonen L; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts., Stengel S; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Tran F; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Das S; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts., Kaser A; Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom., Trajanoski Z; Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria., Blumberg R; Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Roecken C; Department of Pathology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Saur D; Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany., Tschurtschenthaler M; Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany., Schreiber S; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Rosenstiel P; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: p.rosenstiel@mucosa.de., Aden K; Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: k.aden@ikmb.uni-kiel.de.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2022 Jan; Vol. 162 (1), pp. 223-237.e11. Date of Electronic Publication: 2021 Sep 30.
DOI:	10.1053/j.gastro.2021.09.057
Abstrakt:	Background & Aims: Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. Methods: Data from The Cancer Genome Atlas were analyzed for association of XBP1 with colorectal cancer (CRC) survival and molecular interactions between XBP1 and p53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in vitro in mouse models of chronic intestinal epithelial cell (IEC) DNA damage (Xbp1/H2b fl/fl , Xbp1 ΔIEC , H2b ΔIEC , H2b/Xbp1 ΔIEC ) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. Results: In The Cancer Genome Atlas data set of CRC, low XBP1 expression was significantly associated with poor overall survival and reduced p53 pathway activity. In vivo, H2b/Xbp1 ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1 ΔIEC -derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1 fl/fl , H2b ΔIEC , H2b/Xbp1 ΔIEC , and H2b/p53 ΔIEC ) identified a transcriptional program downstream of p53, in which XBP1 directs DNA-damage-inducible transcript 4-like (Ddit4l) expression. DDIT4L inhibits mechanistic target of rapamycin-mediated phosphorylation of 4E-binding protein 1. Pharmacologic mechanistic target of rapamycin inhibition suppressed epithelial hyperproliferation via 4E-binding protein 1. Conclusions: Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L-dependent feedback mechanism. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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