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Folic acid supplementation acts as a chemopreventive factor in tumorigenesis of hepatocellular carcinoma by inducing H3K9Me2-dependent transcriptional repression of LCN2

Yin-Ling Zhang, Geng Xue, Hui Miao, Chuan-Chuan Zhou, Shu-Han Sun and Yi Zhang

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Abstract

Yin-Ling Zhang1,2,*, Geng Xue1,*, Hui Miao1,*, Chuan-Chuan Zhou1, Shu-Han Sun1,2 and Yi Zhang1

1 Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, China

2 Department of Clinical Genetics Division, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China

* These authors contributed equally to this work

Correspondence to:

Yi Zhang,email: xg_smmu@hotmail.com
Shu-Han Sun,email: shsun888@sina.com

Keywords: folic acid; hepatocarcinogenesis; chemoprevention; LCN2; H3K9Me2

Received: February 24, 2017     Accepted: August 26, 2017     Published: February 16, 2021

Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

The effects and mechanisms of folic acid (FA) as a chemopreventive agent for tumorigenesis of hepatocellular carcinoma (HCC) remain unclear. In this study, the QSG-7701, a human normal liver cell line, was cultured in different FA levels (High, Normal or No) for 6 months. Then, the biological characteristics, the expression of main stem cell-like genes or epithelial-mesenchymal transition (EMT) related genes and the tumorigenicity in vivo of cells cultured in different treatment groups were detected. Our results showed that No FA improved the malignant transformation of cells but High FA depressed the malignant transformation. Meanwhile, cells in different treatment groups were mapped by transcriptome sequencing. Then the relativity of increased LCN2 and decreased FA level was identified and confirmed in vitro and vivo. We also revealed that intracellular control of LCN2 would recover the effects of FA on cell proliferation, cell cycle and tumor formation in vitro and vivo. Finally, our studies displayed that increased FA level induced the down-regulation of LCN2 not by DNA hypermethylation of LCN2 promoter but by promoting the level of histone H3 lysine 9 di-methylation (H3K9Me2) in LCN2 promoter. In conclusion, our studies disclosed the chemopreventive effect of FA supplementation on hepatocarcinogenesis, which partial attributed to the inhibition of LCN2 by regulating histone methylation in promoter. Our results provide a potential mechanism of the chemoprevention of FA supplementation on tumorigenesis of HCC and may be helpful in developing treatment target against HCC.


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