Downregulation of UHRF1 Increases Tumor Malignancy by Activating the CXCR4/AKT-JNK/IL-6/Snail Signaling Axis in Hepatocellular Carcinoma Cells

Overview

Journal Sci Rep

Specialty Science

Date 2017 Jun 7

PMID 28584306

Citations 14

Authors

Ji-Hyun Kim

Jae-Woong Shim

Da-Young Eum

Sung Dae Kim

Si Ho Choi

Kwangmo Yang

Kyu Heo

Moon-Taek Park

Affiliations

Soon will be listed here.

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.

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