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

Welz L, Kakavand N, Hang X, Laue G, Ito G, Silva MG, Plattner C, Mishra N, Tengen F, Ogris C, Jesinghaus M, Wottawa F, Arnold P, Kaikkonen L, Stengel S, Tran F, Das S, Kaser A, Trajanoski Z, Blumberg R, Roecken C, Saur D, Tschurtschenthaler M, Schreiber S, Rosenstiel P, Aden K (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Gastroenterology Elsevier

Book Volume: 162

Pages Range: 223-+

Journal Issue: 1

DOI: 10.1053/j.gastro.2021.09.057

Abstract

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(Delta IEC), H2b(Delta IEC), H2b/Xbp1(Delta IEC)) 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(Delta IEC) mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1(Delta IEC)-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1(fl/fl), H2b(Delta IEC), H2b/Xbp1(Delta IEC), and H2b/p53(Delta IEC)) identified a transcriptional pro-gram 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.

Authors with CRIS profile

Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie

Involved external institutions

Christian-Albrechts-Universität zu Kiel DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) DE Germany (DE) Massachusetts General Hospital US United States (USA) (US) University of Cambridge GB United Kingdom (GB) Harvard University US United States (USA) (US) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE)

How to cite

APA:

Welz, L., Kakavand, N., Hang, X., Laue, G., Ito, G., Silva, M.G.,... Aden, K. (2022). Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis. Gastroenterology, 162(1), 223-+. https://doi.org/10.1053/j.gastro.2021.09.057

MLA:

Welz, Lina, et al. "Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis." Gastroenterology 162.1 (2022): 223-+.

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