Abstract
UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.
Highlights
UHRF1 (ubiquitin-like with PHD and RING (Really Interesting New Gene) finger domains 1) contributes to the maintenance of DNA methylation by recruiting DNMT1 to hemimethylated DNA, thereby ensuring that the DNA methylation patterns of mother cells are correctly imparted to daughter cells[1]
To validate our previous report[25], we investigated whether UHRF1 deficiency is associated with the acquisition of mesenchymal characteristics in hepatocellular carcinoma cells
The ability of human fetal hepatocytes (HFHs) and Huh[7] cells to migrate and invade was substantially greater than that of HepG2 and Hep3B cells, indicating that the downregulation of UHRF1 may be related to an increase in cell migratory/invasive ability and processes that are involved in epithelial-mesenchymal transition (EMT) (Fig. 1a and b)
Summary
UHRF1 (ubiquitin-like with PHD (plant homeodomain) and RING (Really Interesting New Gene) finger domains 1) contributes to the maintenance of DNA methylation by recruiting DNMT1 to hemimethylated DNA, thereby ensuring that the DNA methylation patterns of mother cells are correctly imparted to daughter cells[1]. The ability of HFHs and Huh[7] cells to migrate and invade was substantially greater than that of HepG2 and Hep3B cells, indicating that the downregulation of UHRF1 may be related to an increase in cell migratory/invasive ability and processes that are involved in EMT (Fig. 1a and b). As UHRF1 downregulation increased both migration and invasion in vitro and is involved in hypoxia-induced EMT, we investigated whether it contributes to tumor growth in vivo.
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