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

Welz, Lina; Kakavand, Nassim; Hang, Xiang; Laue, Georg; Ito, Go; Silva, Miguel Gomes; Plattner, Christina; Mishra, Neha; Tengen, Felicitas; Ogris, Christoph; Jesinghaus, Moritz; Wottawa, Felix; Arnold, Philipp; Kaikkonen, Leena; Stengel, Stefanie; Tran, Florian; Das, Saumya; Kaser, Arthur; Trajanoski, Zlatko; Blumberg, Richard; Roecken, Christoph; Saur, Dieter; Tschurtschenthaler, Markus; Schreiber, Stefan; Rosenstiel, Philip; Aden, Konrad

doi:10.1053/j.gastro.2021.09.057

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Title:: Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis.
Document type:: Journal Article
Author(s):: Welz, Lina; Kakavand, Nassim; Hang, Xiang; Laue, Georg; Ito, Go; Silva, Miguel Gomes; Plattner, Christina; Mishra, Neha; Tengen, Felicitas; Ogris, Christoph; Jesinghaus, Moritz; Wottawa, Felix; Arnold, Philipp; Kaikkonen, Leena; Stengel, Stefanie; Tran, Florian; Das, Saumya; Kaser, Arthur; Trajanoski, Zlatko; Blumberg, Richard; Roecken, Christoph; Saur, Dieter; Tschurtschenthaler, Markus; Schreiber, Stefan; Rosenstiel, Philip; Aden, Konrad
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/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) 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/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, and H2b/p53ΔIEC) 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.
Journal title abbreviation:: Gastroenterology
Year:: 2022
Journal volume:: 162
Journal issue:: 1
Pages contribution:: 223-237.e11
Fulltext / DOI:: doi:10.1053/j.gastro.2021.09.057
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/34599932
Print-ISSN:: 0016-5085
TUM Institution:: Institut für Allgemeine Pathologie und Pathologische Anatomie; Lehrstuhl für Experimentelle Tumortherapie (Prof. Saur)
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