Downregulation of UHRF1 increases tumor malignancy by activating the CXCR4/AKT-JNK/IL-6/Snail signaling axis in hepatocellular carcinoma cells

• Published in: Scientific reports 2017-06, Vol.7 (1), p.2798-16, Article 2798
• Main Authors: Kim, Ji-Hyun, Shim, Jae-Woong, Eum, Da-Young, Kim, Sung Dae, Choi, Si Ho, Yang, Kwangmo, Heo, Kyu, Park, Moon-Taek
• Format: Article
• Language: English
• Subjects: 13/31; 13/95; 14/19; 42/41; 45/15; 45/77; 631/67/322; 631/80/84/2176; 96/1; 96/21; AKT protein; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CCAAT-Enhancer-Binding Proteins - deficiency; CCAAT-Enhancer-Binding Proteins - genetics; Chromatin remodeling; CXCR4 protein; DNA methylation; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Gene expression; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Hypoxia; Interleukin 6; Interleukin-6 - metabolism; Invasiveness; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Malignancy; Mesenchyme; multidisciplinary; Neoplastic Stem Cells - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CXCR4 - metabolism; Science; Science (multidisciplinary); Signal Transduction; Snail Family Transcription Factors - metabolism; Stat3 protein; Ubiquitin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02935-2

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.