Abstract 6300: Cyprohepatdine, an anti-histamine and epigenetic modifier, reverses epigenetic silencing of the tumor suppressor IRF6 in urothelial carcinoma

Abstract

Abstract Urothelial carcinoma (UC) is the most common malignancy of the urinary system. We have previously demonstrated that cyproheptadine (CPH), an anti-histamine, inhibited UC tumor growth in vitro and in vivo. However, the exact mechanism of how CPH inhibited tumor growth is not fully understood. In this study, we performed RNA-Seq in control BFTC905 UC cells and cells treated with CPH. The results showed that several genes, including IRF6 (interferon regulator factor 6), showing differential upregulation after CPH treatment. Real-time RT-PCR confirmed the restoration of IRF6 expression in a panel of UC cell lines treated with CPH. Similar to 5azaDC, bisulphite pyrosequencing found that CPH could decrease promoter methylation of IRF6 in UC cell lines. Interestingly, CPH could also increase total mono-methylation of H3K4 and acetylation of H3K27. Functional studies found that ectopic expression of IRF6 suppressed UC tumor growth in vitro and in vivo. Clinical studies also found that high-grade UC patient tissue samples has significantly higher IRF6 methylation than low-grade tumor samples. Taken together, our results suggested that CPH may be a novel epigenetic modifier exhibiting both DNMTi and HDACi activities in UC. The therapeutic potential of CPH in the treatment of UC deserves further investigation. Citation Format: Michael W.Y. Chan, Pie-Che Chen, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Hon-Yi Lin, Yeong-Chin Jou, Cheng-Huang Shen. Cyprohepatdine, an anti-histamine and epigenetic modifier, reverses epigenetic silencing of the tumor suppressor IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6300.