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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.

Original publication

DOI

10.1038/s41467-018-07306-7

Type

Journal article

Journal

Nat Commun

Publication Date

14/11/2018

Volume

9

Keywords

Animals, Cell Adhesion, Cell Movement, Citrullination, Collagen Type I, Colorectal Neoplasms, Epithelial-Mesenchymal Transition, Extracellular Matrix, HCT116 Cells, HT29 Cells, Humans, Hydrolases, Liver Neoplasms, Mice, Neoplasm Metastasis, Protein-Arginine Deiminase Type 4, Protein-Arginine Deiminases