The role of cyproheptadine as an epigenetic modifier in restoring innate immune response in urothelial carcinoma

• Main Authors: YEH, CHIH-CHIEH, 葉智傑
• Other Authors: CHAN, MICHAEl WING-YAN
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/4x6rqz

碩士 === 國立中正大學 === 生命科學系生物醫學研究所 === 106 === Urothelial carcinoma (UC), a complex and heterogeneous disease caused by both genetic, epigenetic and environmental factor, is one of the most common cancer in the world and second most common malignancy of the urinary system with high rate of recurrence. Therefore, UC patients need to be treated intensively by surgical or therapeutic approach. However, targeted therapy is not currently available. Our previous study showed that cyproheptadine (CPH), an anti-histamine and serotonin antagonist, inhibited tumor growth in human UC cells both in vitro and in an animal model. Previous RNA sequencing experiments found that the anti-tumor activity may be contributed from the upregulation of UL16 Binding Protein 2 (ULBP2), a MHC class I-related molecule and ligand for NK cell receptor, after treatment with CPH. We therefore aimed to identify the effect of CPH in the epigenetic modification of ULBP2 and the role of CPH and ULBP2 in the anti-tumor immune response in UC. ULBP2 re-expression could be confirmed by qRT-PCR in UMUC3 and BFTC905 UC cell lines treated with CPH as well as using HDAC inhibitor. Importantly, the re-expression of ULBP2 was in concomitant to the enrichment of H3K27Ac and H3K4me3 in the promoter region of ULBP2 in CPH treated BFTC905 cells. Interestingly, we tested HDAC inhibitor or CPH for their ability to re-expressed ULBP2 in enhancing in UC eradication by NK cells and found that ULBP2 was epigenetically silenced by histone modification. In conclusion, CPH could be a novel epigenetic modifier in modifying the histone modifications in re-expression of ULBP2 in enhancing NK eradication in UC. Future experiments in understanding the role of CPH in restoring innate anti-tumor immune response in UC are currently being investigated.