Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development

Mingyu Lee, Yi-Sook Kim, Suha Lim, Seung-Hyun Shin, Iljin Kim, Jiyoung Kim, Min Choi, Jung Ho Kim, Seong-Joon Koh, Jong-Wan Park and Hyun-Woo Shin ()
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Mingyu Lee: Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School
Yi-Sook Kim: Seoul National University Graduate School
Suha Lim: Seoul National University Graduate School
Seung-Hyun Shin: Hanmi Research Center, Hanmi Pharmaceutical Co. Ltd.
Iljin Kim: Inha University College of Medicine
Jiyoung Kim: Seoul National University Graduate School
Min Choi: Seoul National University Graduate School
Jung Ho Kim: Seoul National University Hospital, Seoul National University College of Medicine
Seong-Joon Koh: Liver Research Institute and Seoul National University College of Medicine
Jong-Wan Park: Seoul National University Graduate School
Hyun-Woo Shin: Seoul National University Graduate School

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Date: 2023
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DOI: 10.1038/s41467-023-38080-w

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