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Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells

Oncogene volume 38, pages 6051–6064 (2019)Cite this article

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Abstract

Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the β-catenin/TCF7L2 complex. Although genes upregulated by Wnt/β-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/β-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/β-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/β-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/β-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.

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Acknowledgements

We are grateful to Seira Hatakeyama, Rika Koubo, Tomoko Isobe and Yumiko Ishii (The University of Tokyo) for their technical assistance.

Funding

This work was supported in part by JSPS KAKENHI Grant numbers JP17H03575 (Y.F.) and the Sasakawa Scientific Research Grant (Grant numbers 29-435, T.O.) from the Japan Science Society.

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  1. These authors contributed equally: Tomoyuki Ohsugi, Kiyoshi Yamaguchi

Authors and Affiliations

  1. Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan

    Tomoyuki Ohsugi, Kiyoshi Yamaguchi, Chi Zhu, Tsuneo Ikenoue, Kiyoko Takane & Yoichi Furukawa

  2. Department of Surgery, IMSUT Hospital, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan

    Masaru Shinozaki & Giichiro Tsurita

  3. Department of Surgery, Center Hospital of the National Center for Global Health and Medicine, Tokyo, 162-8655, Japan

    Hideaki Yano

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TO and KY performed experiments. TO, CZ, KT, KY, TI, and YF provided interpretation of the data. MS, GT, and HY collected and analyzed clinical samples. TO wrote the draft of the manuscript, and KY and YF revised the manuscript. All authors have approved this manuscript.

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Ohsugi, T., Yamaguchi, K., Zhu, C. et al. Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells. Oncogene 38, 6051–6064 (2019). https://doi.org/10.1038/s41388-019-0856-9

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