Ulcerative Colitis (UC) is a chronic, relapsing inflammatory bowel disease that affects millions of people worldwide. As a result of DNA damage caused by the chronic inflammatory state of UC, people suffering from UC are at a higher risk of developing colorectal cancer (CRC). Although the cause of UC is still unknown, the protein arginine deiminase (PAD) family of enzymes has been found to be a key component in many human inflammatory diseases and cancer, including UC and CRC. PADs are calcium-dependent enzymes that post-translationally convert positively charged peptidyl-Arginine to neutral peptidyl-Citrulline through a process called ‘citrullination’. In hopes of treating UC and preventing CRC, we developed Chlor-amidine (Cl-amidine), a novel small molecule inhibitor of PADs. Previous results from our group have shown that miR-16, which is often downregulated in cancers, had increased expression levels in mice treated with Cl-amidine. MiR-16 targets (i.e. Cyclin D1 and E1) and colon carcinogenesis were also suppressed in mice treated with Cl-amidine. Our goal is to determine the mechanism(s) by which Cl-amidine targets miR-16 and other tumor suppressor miRNAs. One hypothesis is that Cl-amidine is preventing the citrullination of DNA methyltransferases (DNMTs). Citrullinated DNMTs show hyperactivity, resulting in hypermethylation and subsequent silencing of miRNAs. Evidence suggests that PADs can citrullinate DNMT3A, resulting in ‘methylation-mediated gene silencing’. We predict that this silencing negatively regulates tumor suppressor miRNAs and Cl-amidine treatment will restore these miRNA levels. Initial results suggest citrullination of DNMT3A in our in vitro colon cancer cell line model. Experiments are ongoing to confirm the ability of Cl-amidine to prevent citrullination-induced activation of upstream miRNA regulators. Results from our study will elaborate on the mechanism of action of Cl-amidine and provide further insight into using Cl-amidine as an anti-cancer therapy.

Citation Format: Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth. Citrullination of miRNA regulators by PADs: A potential mechanism for the promotion of colitis and colitis-associated colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 238. doi:10.1158/1538-7445.AM2015-238

©2015 American Association for Cancer Research.
2015