Abstract 2243: Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma

Abstract Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. In this study, we performed RNA-Seq to examine genes that are differentially expressed after treatment with CPH in UC cells. Our result showed that several genes, including IRF6, were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, which is due to promoter hypomethylation and enrichment of H3K27 acetylation, as well as H3K4 mono-methylation. Importantly, treatment of CPH can inhibit tumor growth in a syngeneic mouse tumor model. The tumor growth can be further inhibited by combination treatment of CPH and immune checkpoint blockade. Flow cytometric analysis of the tumor found that NK cells are significantly enriched in the CPH treatment group, as compared to DMSO control. Co-culture experiments confirmed that UC cells pretreated with CPH showed an increased NK-92-mediated cytotoxicity. In conclusion, these results suggested that treatment of CPH can inhibit tumor growth, by epigenetic priming of IRF6 in UC. The role of CPH in eliciting anti-tumor innate immune response deserves further investigation. Citation Format: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan. Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2243.