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Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma

BACKGROUND: 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...

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Autores principales: Jou, Yeong-Chin, Lin, Guan-Ling, Lin, Hon-Yi, Huang, Wan-Hong, Chuang, Yu-Ming, Lin, Ru-Inn, Chen, Pie-Che, Wu, Shu-Fen, Shen, Cheng-Huang, Chan, Michael W. Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054409/
https://www.ncbi.nlm.nih.gov/pubmed/33874979
http://dx.doi.org/10.1186/s12935-021-01925-9
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author Jou, Yeong-Chin
Lin, Guan-Ling
Lin, Hon-Yi
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Chen, Pie-Che
Wu, Shu-Fen
Shen, Cheng-Huang
Chan, Michael W. Y.
author_facet Jou, Yeong-Chin
Lin, Guan-Ling
Lin, Hon-Yi
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Chen, Pie-Che
Wu, Shu-Fen
Shen, Cheng-Huang
Chan, Michael W. Y.
author_sort Jou, Yeong-Chin
collection PubMed
description BACKGROUND: 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. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood. METHODS: Genes 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. RESULTS: 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, 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. CONCLUSION: In 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-021-01925-9.
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spelling pubmed-80544092021-04-20 Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma Jou, Yeong-Chin Lin, Guan-Ling Lin, Hon-Yi Huang, Wan-Hong Chuang, Yu-Ming Lin, Ru-Inn Chen, Pie-Che Wu, Shu-Fen Shen, Cheng-Huang Chan, Michael W. Y. Cancer Cell Int Primary Research BACKGROUND: 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. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood. METHODS: Genes 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. RESULTS: 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, 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. CONCLUSION: In 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-021-01925-9. BioMed Central 2021-04-19 /pmc/articles/PMC8054409/ /pubmed/33874979 http://dx.doi.org/10.1186/s12935-021-01925-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Primary Research
Jou, Yeong-Chin
Lin, Guan-Ling
Lin, Hon-Yi
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Chen, Pie-Che
Wu, Shu-Fen
Shen, Cheng-Huang
Chan, Michael W. Y.
Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title_full Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title_fullStr Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title_full_unstemmed Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title_short Cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
title_sort cyproheptadine, an epigenetic modifier, exhibits anti-tumor activity by reversing the epigenetic silencing of irf6 in urothelial carcinoma
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054409/
https://www.ncbi.nlm.nih.gov/pubmed/33874979
http://dx.doi.org/10.1186/s12935-021-01925-9
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