Cellular and Molecular Gastroenterology and Hepatology (Jan 2025)

Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary

  • Kensuke Hamada,
  • Yuki Nakanishi,
  • Yu Muta,
  • Mayuki Omatsu,
  • Kosuke Iwane,
  • Munehiro Ikeda,
  • Jiayu Chen,
  • Yoko Masui,
  • Naoki Aoyama,
  • Nobukazu Agatsuma,
  • Go Yamakawa,
  • Takahiro Utsumi,
  • Hiroki Kitamoto,
  • Makoto Okabe,
  • Yoshiro Itatani,
  • Takumi Adachi,
  • Koubun Yasuda,
  • Shuji Yamamoto,
  • Akihisa Fukuda,
  • Etsushi Kuroda,
  • Masaki Ohmuraya,
  • Kazutaka Obama,
  • Seiichi Hirota,
  • Hiroki Ikeuchi,
  • Kenji Nakanishi,
  • Hiroshi Seno

Journal volume & issue
Vol. 19, no. 3
p. 101435

Abstract

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Background & Aims: Retinoblastoma-binding protein 9 (RBBP9) was initially reported as cell cycle regulator via RB/E2F. Accumulating evidence has revealed the importance of RBBP9 in physiological and pathological states including inflammatory disease. However, the functional role of RBBP9 in ulcerative colitis (UC) and colitis-associated cancer (CAC) remains elusive. Methods: Human samples of UC and CAC were examined by immunohistochemical and bioinformatics analyses. We established dextran sodium sulfate (DSS)-induced colitis, azoxymethane (AOM)/DSS-induced CAC model, and ApcMin/+ sporadic tumor model using wild-type and Rbbp9-/- mice. RNA sequencing was analyzed to identify the phenotype alternation upon Rbbp9 deletion. In addition, genetic and pharmacological inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) pathway was performed. Results: The expression of RBBP9 was reduced in human UC and CAC samples. The loss of RBBP9 enhanced the activation of interferon (IFN)/JAK/STAT1 signaling, resulting in susceptibility to DSS-induced colitis and AOM/DSS-induced CAC tumors by increasing epithelial cell apoptosis and immune activation. An in vitro kinase assay revealed that RBBP9 directly regulated JAK/STAT1 signaling by suppressing STAT1 phosphorylation. A positive feedback loop involving epithelial cell apoptosis, commensal microbiome invasion, and activation of submucosal immune activity was identified in Rbbp9-/- mouse intestines through enhanced JAK/STAT1 signaling in RBBP9-deficient epithelial cells and macrophages. The genetic inhibition of STAT1 or treatment with the JAK/STAT inhibitor reversed epithelial cell apoptosis and mitigated the enhanced susceptibility to DSS-induced colitis in Rbbp9-/- mice. Conclusions: RBBP9 suppresses the intestinal inflammation by negatively regulating JAK/STAT1 signaling pathway.

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