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Inhibitory effect of bound polyphenol from foxtail millet bran on miR-149 methylation increases the chemosensitivity of human colorectal cancer HCT-8/Fu cells

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Abstract

Nature polyphenols widely present in plants and foods are promising candidates in cancer chemotherapy. Emerging evidence has shown that plant polyphenols regulate the expression of miRNAs to exert the anti-Multidrug resistance (MDR) activity, which partly attributes to their regulation on miRNAs methylation. Our previous study found that bound polyphenol from foxtail millet bran (BPIS) had potential as an anti-MDR agent for colorectal cancer (CRC), but its mechanism remains unclear. The present findings demonstrated that BPIS upregulated the expression of miR-149 by reducing the methylation of its CpG islands, which subsequently induced the cell cycle arrest in G2/M phase, resulting in enhancing the chemo-sensitivity of HCT-8/Fu cells. Mechanically, BPIS and its active components (FA and p-CA) reduced miR-149 methylation by inhibiting the expression levels of DNA methyltransferases, promoting a remarkable increase of miR-149 expression. Further, the increased miR-149 induced cell cycle arrest in G2/M phase by inhibiting the expression of Akt, Cyclin B1 and CDK1, thus increasing the chemosensitivity of HCT-8/Fu cells. Additionally, a strong inducer of DNA de-methylation (5-aza-dc) treatment markedly increased the chemosensitivity of CRC through elevating miR-149 expression, which indicates the hypermethylation of miR-149 may be the key cause of drug resistance in CRC. The study indicates that the enhanced chemosensitivity of BPIS on CRC is mainly attributed to the increase of miR-149 expression induced by methylation inhibition.

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Abbreviations

ANOVA:

Analysis of variance

BPIS:

Bound polyphenol from foxtail millet bran

CRC:

Colorectal cancer

DNMTs:

DNA methyltransferases

DMSO:

Dimethyl sulphoxide

FBS:

Fetal bovine serum

FA:

Ferulic acid

MDR:

Multidrug resistance

MSP:

Methylation-specific PCR

p-CA:

P-coumaric acid

PVDF:

Polyvinylidene fluoride

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 31770382, 81803238), “1331 Project” Key Innovation Center and Team of Shanxi Province, Shanxi Province Science Foundation for Key Projects (No. 201801D111001), Shanxi Province Science Foundation for Youths (No. 201901D211143), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (No. 2019L0016), Shanxi Key Laboratory for Research and Development of Regional Plants, Collaborative Innovation Center of Quality and Efficiency of Loess Plateau Edible Fungi in Shanxi.

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  1. Shuhua Shan and Yang Lu have contributed equally to this work.

Authors and Affiliations

  1. Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China

    Shuhua Shan, Yang Lu, Xiaoli Zhang, Jiangying Shi & Zhuoyu Li

  2. School of Life Science, Shanxi University, Taiyuan, China

    Hanqing Li & Zhuoyu Li

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  1. Shuhua Shan
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Correspondence to Zhuoyu Li.

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Shan, S., Lu, Y., Zhang, X. et al. Inhibitory effect of bound polyphenol from foxtail millet bran on miR-149 methylation increases the chemosensitivity of human colorectal cancer HCT-8/Fu cells. Mol Cell Biochem 476, 513–523 (2021). https://doi.org/10.1007/s11010-020-03906-4

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