Abstract
BackgroundUrothelial 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. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood.MethodsGenes that were upregulated after treatment with CPH in UC cells, were examined by RNA-Seq. Real-time quantitative PCR (RT-qPCR) was employed to detect IRF6 expression while COBRA assay and bisulphite pyrosequencing were used to examine promoter methylation of IRF6. Enrichment of total H3K27 acetylation and H3K4 mono-methylation were detected by western blotting. Colony formation and flow cytometry were used to examine proliferation and apoptosis in UC cells overexpressed or depleted with IRF6. Nude mice xenograft model was used to examine the effect of IRF6 in UC.ResultsOur 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, probably due to promoter hypomethylation and enrichment of H3K27 acetylation and H3K4 mono-methylation. These results may be due to the fact that CPH could alter the activity, but not the expression of epigenetic modifiers. Finally, re-expression of IRF6 in UC inhibited tumor growth in vitro and in an xenograft mouse model, by inducing apoptosis.ConclusionIn conclusion, our results suggested that CPH may be an epigenetic modifier, modulating the expression of the potential tumor suppressor IRF6, in inhibiting tumor growth in UC.
Highlights
Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients needed to be treated with surgery followed by chemotherapy
Majority of UC patients are diagnosed with non-muscleinvasive bladder cancer (NMIBC), patients may recur with muscle invasive tumor (MIBC)
IRF6 was upregulated after treatment with CPH in UC cells To investigate the detailed mechanism of how CPH inhibited tumor progression, RNA-Seq was performed to identify gene expression profile of BFTC905 cells treated with 55 μM CPH for 24 h, as BFTC905 cells exhibited a higher CPH-induced apoptotic response in our previous study [12]
Summary
Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients needed to be treated with surgery followed by chemotherapy. Bladder cancer is the second most common malignancy of the genitourinary system, in which majority comprises of urothelial carcinoma (UC) [1, 2]. Higher overall response rate using immune checkpoint blockade (ICB) is only limited to patient with higher expression of PD-L1 in tumor [8]. In this regard, development of novel therapy target for UC is an urgent issue
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