Estrogen-induced epigenetic silencing of FTH1 and TFRC genes reduces liver cancer cell growth and survival. Issue 12 (1st December 2020)

• Record Type: Journal Article
• Authors: Muhammad, Jibran Sualeh; Bajbouj, Khuloud; Shafarin, Jasmin; Hamad, Mawieh
• Is Part Of: Epigenetics. Volume 15:Issue 12(2020)
• Page Start: 1302
• Page End: 1318
• Publication Date: 2020-12-01
• Subjects: DNA methylation -- Histone methylation -- Liver cancer -- Estrogen -- Iron-regulatory genes; Epigenesis -- Periodicals; Epigenetica; 572.86505
• DOI: 10.1080/15592294.2020.1770917
• Languages: English
• ISSNs: 1559-2294

Abstract

ABSTRACT: Estrogen (E2) regulates hundreds of genes involved in cell metabolism and disrupts iron homoeostasis in various cell types. Herein, we addressed whether E2-induced epigenetic modifications are involved in modulating the expression of iron-regulatory genes. Epigenetic status of FTH1 and TFRC genes was assessed in E2-treated cancer cells. E2-induced DNA methylation was associated with decreased FTH1 and TFRC expression in Hep-G2 and Huh7 cells, but not in AGS or MCF7 cells. Demethylation with 5-Aza-2-deoxycytidine upregulated the expression of both these genes in Hep-G2 cells. The expression of DNMT3B, PRMT5, and H4R3me2s increased in E2-treated cells. Chromatin immunoprecipitation showed that E2 treatment recruited PRMT5 and H4R3me2s on FTH1 but not on TFRC . Knockdown of PRMT5, DNMT3B, and Estrogen-receptor alpha rescued FTH1 from E2-induced silencing. However, knockdown of DNMT3B alone blocked the inhibitory effects of E2 on TFRC . Analysis of human liver tissues in publicly available datasets showed that FTH1 and TFRC are highly expressed in primary liver tumours, but a lower expression is associated with better survival. Interestingly, we showed that the silencing of FTH1 and/or TFRC inhibited carcinogenesis in Hep-G2 cells. For the first time, our findings uncovered the novel signalling pathway involved in the protective effects of E2 against liver cancer. Graphical Abstract: