Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation

BackgroundCancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkalo...

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Autores principales:	Ziyi Zhao, Jinhao Zeng, Qiang Guo, Kunming Pu, Yi Yang, Nianzhi Chen, Gang Zhang, Maoyuan Zhao, Qiao Zheng, Jianyuan Tang, Qiongying Hu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	cancer stem-like cells (CSCs) Berberine m6A methylation β-catenin FTO Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/33b0cd7f60084dfa89691366bf345b89
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spelling	oai:doaj.org-article:33b0cd7f60084dfa89691366bf345b892021-11-15T04:29:19ZBerberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation2234-943X10.3389/fonc.2021.775418https://doaj.org/article/33b0cd7f60084dfa89691366bf345b892021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.775418/fullhttps://doaj.org/toc/2234-943XBackgroundCancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms.MethodsIn this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating β-catenin.ResultsWe examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing β-catenin, which is a negative regulator of FTO.ConclusionsOur observation that Berberine effectively decreased m6A methylation by decreasing β-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.Ziyi ZhaoZiyi ZhaoJinhao ZengJinhao ZengQiang GuoKunming PuYi YangNianzhi ChenGang ZhangMaoyuan ZhaoQiao ZhengJianyuan TangJianyuan TangQiongying HuFrontiers Media S.A.articlecancer stem-like cells (CSCs)Berberinem6A methylationβ-cateninFTONeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer stem-like cells (CSCs) Berberine m6A methylation β-catenin FTO Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cancer stem-like cells (CSCs) Berberine m6A methylation β-catenin FTO Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ziyi Zhao Ziyi Zhao Jinhao Zeng Jinhao Zeng Qiang Guo Kunming Pu Yi Yang Nianzhi Chen Gang Zhang Maoyuan Zhao Qiao Zheng Jianyuan Tang Jianyuan Tang Qiongying Hu Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
description	BackgroundCancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms.MethodsIn this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating β-catenin.ResultsWe examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing β-catenin, which is a negative regulator of FTO.ConclusionsOur observation that Berberine effectively decreased m6A methylation by decreasing β-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.
format	article
author	Ziyi Zhao Ziyi Zhao Jinhao Zeng Jinhao Zeng Qiang Guo Kunming Pu Yi Yang Nianzhi Chen Gang Zhang Maoyuan Zhao Qiao Zheng Jianyuan Tang Jianyuan Tang Qiongying Hu
author_facet	Ziyi Zhao Ziyi Zhao Jinhao Zeng Jinhao Zeng Qiang Guo Kunming Pu Yi Yang Nianzhi Chen Gang Zhang Maoyuan Zhao Qiao Zheng Jianyuan Tang Jianyuan Tang Qiongying Hu
author_sort	Ziyi Zhao
title	Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
title_short	Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
title_full	Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
title_fullStr	Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
title_full_unstemmed	Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
title_sort	berberine suppresses stemness and tumorigenicity of colorectal cancer stem-like cells by inhibiting m6a methylation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/33b0cd7f60084dfa89691366bf345b89
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Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation

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