Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Cell Biology | Digestive System Diseases | Enzymes and Coenzymes
Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.
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Copyright © The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Nat Commun. 2018 Nov 14;9(1):4783. doi: 10.1038/s41467-018-07306-7. Link to article on publisher's site
Yuzhalin AE, Gordon-Weeks AN, Tognoli ML, Jones K, Markelc B, Konietzny R, Fischer R, Muth A, O'Neill E, Thompson PR, Venables PJ, Kessler BM, Lim SY, Muschel RJ. (2018). Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix. Open Access Publications by UMass Chan Authors. https://doi.org/10.1038/s41467-018-07306-7. Retrieved from https://escholarship.umassmed.edu/oapubs/3675
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.