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

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.

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

“…JNK are extremely important in the process of apoptotic cell death as one subgroup of the MAPK family. JNK and ERK, as stress‐activated protein kinases, are activated by various stress stimuli, such as bioactive compounds, to induce apoptosis . Consistent with these results, we observed that JNK activation and ERK1/2 activation were involved in RA‐induced apoptosis in a drug concentration‐ and time‐dependent method.…”

Evaluation of UHRF1 and P16INK4A expression levels in newly diagnosed AML patients

“…Therefore, regarding our data, UHRF1 down-regulation can be a possible mechanism, underlying DNMT overexpression in AML patients, which is consistent with genomic hypermethylation that occurs in many TSG regions of AML blasts 9 . Additionally, other studies on human hepatocellular carcinoma cell lines have demonstrated that UHRF1 deficiency led to an expansion of cancer cells by CXCR4/AKT-JNK/IL-6 signaling pathway activation 29 . Furthermore, we also detected a significant positive correlation between the age of AML patients and UHRF1 gene expression levels (r=0.397 and p=0.005).…”

CoCl2, a mimic of hypoxia, enhances bone marrow mesenchymal stem cells migration and osteogenic differentiation via STAT3 signaling pathway

“…The JNK, FAK, and ERK1/2 pathways are closely related to cell migration as well as communicated with STAT3 pathway (Thakur et al, ; Xing et al, ; Kim et al, ; Li et al, ). We found that hypoxia enhanced phosphorylation of ERK1/2 in BMSCs.…”

“…Our previous study demonstrated that the STAT3 pathway enhances pre‐osteoclasts migration (Li et al, ). The STAT3 pathway communicates with Jun N‐terminal kinase (JNK) and chemokine receptor (CXCR) 4 pathways to adjust the migration of hepatocellular carcinoma cells (Kim et al, ). Similarly, focal adhesion kinase (FAK) and STAT3 are involved in migration of breast cancer cells (Thakur et al, ).…”