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Welz, L.* ; Kakavand, N.* ; Hang, X.* ; Laue, G.* ; Ito, G.* ; Silva, M.G.* ; 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.*

Epithelial XBP1 coordinates TP53-driven DNA damage responses and suppression of intestinal carcinogenesis.

Gastroenterology 162, 223-237.e11 (2021)

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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 towards 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 TCGA were analyzed for association of XBP1 with CRC survival and molecular interactions between XBP1 andp53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in-vitro, in mouse models of chronic intestinal epithelial 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 TCGA dataset of CRC, low XBP1 expression was significantly associated with poor overall survival (OS) 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, H2b/p53^ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA damage-induced Ddit4l expression. DDIT4L inhibits mTOR-mediated phosphorylation of 4E-BP1. Pharmacological mTOR inhibition suppressed epithelial hyperproliferation via 4E-BP1. 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Crc ; Dna Damage ; Xbp1 ; Intestinal Epithelial Cell ; P53; Strand Break Repair; Colorectal-cancer; Er Stress; Progression; Mutations; Tumorigenesis; Inflammation; Disease; Cells; Model

ISSN (print) / ISBN 0016-5085

e-ISSN 1528-0012

Journal Gastroenterology

Quellenangaben Volume: 162, Issue: 1, Pages: 223-237.e11

Publisher Elsevier

Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)