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

Gastroenterology. 2022 Jan;162(1):223-237.e11. doi: 10.1053/j.gastro.2021.09.057. Epub 2021 Sep 30.

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.

Keywords: CRC; DNA Damage; Intestinal Epithelial Cell; XBP1; p53.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adenoma / drug therapy
  • Adenoma / genetics
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA Damage*
  • Databases, Genetic
  • Endoplasmic Reticulum Stress
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestinal Neoplasms / drug therapy
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism*
  • Intestinal Neoplasms / pathology
  • MTOR Inhibitors / pharmacology
  • Mice
  • Mice, Knockout
  • Signal Transduction
  • Sirolimus / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Ddit4l protein, mouse
  • Eif4ebp1 protein, mouse
  • MTOR Inhibitors
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Sirolimus