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Nat Chem Biol. 2018 Jan;14(1):94-101. doi: 10.1038/nchembio.2510. Epub 2017 Oct 30.

Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer.

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Department of Clinical Science, University of Bergen, Bergen, Norway.
Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai, P.R. China.
Department of Dermatology, University of Zürich, University of Zürich Hospital, Zürich, Switzerland.
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.


Wnt (wingless)/β-catenin signaling is critical for tumor progression and is frequently activated in colorectal cancer as a result of the mutation of adenomatous polyposis coli (APC); however, therapeutic agents targeting this pathway for clinical use are lacking. Here we report that nitazoxanide (NTZ), a clinically approved antiparasitic drug, efficiently inhibits Wnt signaling independent of APC. Using chemoproteomic approaches, we have identified peptidyl arginine deiminase 2 (PAD2) as the functional target of NTZ in Wnt inhibition. By targeting PAD2, NTZ increased the deamination (citrullination) and turnover of β-catenin in colon cancer cells. Replacement of arginine residues disrupted the transcriptional activity, and NTZ induced degradation of β-catenin. In Wnt-activated colon cancer cells, knockout of either PAD2 or β-catenin substantially increased resistance to NTZ treatment. Our data highlight the potential of NTZ as a modulator of β-catenin citrullination for the treatment of cancer patients with Wnt pathway mutations.

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