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

• Published in: Cellular and molecular gastroenterology and hepatology 2024-12, p.101435, Article 101435
• Main Authors: Hamada, Kensuke, Nakanishi, Yuki, Muta, Yu, Omatsu, Mayuki, Iwane, Kosuke, Ikeda, Munehiro, Chen, Jiayu, Masui, Yoko, Aoyama, Naoki, Agatsuma, Nobukazu, Yamakawa, Go, Utsumi, Takahiro, Kitamoto, Hiroki, Okabe, Makoto, Itatani, Yoshiro, Adachi, Takumi, Yasuda, Koubun, Yamamoto, Shuji, Fukuda, Akihisa, Kuroda, Etsushi, Ohmuraya, Masaki, Obama, Kazutaka, Hirota, Seiichi, Ikeuchi, Hiroki, Nakanishi, Kenji, Seno, Hiroshi
• Format: Article
• Language: English
• Subjects: Colitis-associated Cancer; Interferon Signaling; Retinoblastoma-binding Protein 9; Ulcerative Colitis
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2024.101435

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. 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. 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. RBBP9 suppresses the intestinal inflammation by negatively regulating JAK/STAT1 signaling pathway. [Display omitted]