Inhibitory effect of bound polyphenol from foxtail millet bran on miR-149 methylation increases the chemosensitivity of
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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 Shuhua Shan1 · Yang Lu1 · Xiaoli Zhang1 · Jiangying Shi1 · Hanqing Li2 · Zhuoyu Li1,2 Received: 7 April 2020 / Accepted: 7 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Foxtail millet bran · Bound polyphenol · Chemosensitivity · miR-149 methylation · Colorectal cancer cells 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 Shuhua Shan and Yang Lu have contributed equally to this work. * Zhuoyu Li [email protected] 1
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China
School of Life Science, Shanxi University, Taiyuan, China
2
Introduction Colorectal cancer (CRC) is the most aggressive gastrointestinal cancer. According to Global Cancer Data Statistics in 2018, CRC is the second-leading cause of death among all cancers [1]. Clinically, the current common chemotherapeutic drugs for CRC patients are 5-fluorouracil (5-Fu), vincristine (VCR) and oxaliplatin (L-OHP). However, majority of patients will eventu
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