Downregulation of UHRF1 promotes EMT via inducing CXCR4 in human cancer cells

Abstract

Activation of epithelial-mesenchymal transition (EMT) is important for malignant tumor progression exhibiting migratory and invasive properties. UHRF1 (ubiquitin-like, with PHD and RING finger domains 1), as an epigenetic regulator, plays a crucial role in DNA CpG methylation, chromatin remodeling and gene expression. Many studies demonstrated that UHRF1 is aberrantly expressed in various types of human cancer. However, the precise role of UHRF1 in human cancers remains highly controversial. In the present study, we found that downregulation of UHRF1 enhances the migratory and invasive properties of human cancer cells by inducing EMT, and that the CXCR4 signaling pathway is strictly necessary for UHRF1 deficiency-mediated induction of EMT. Downregulation of UHRF1 induced the expression of the EMT-regulating transcription factors, Zeb1, Slug and Snail and then led to decreased protein level of E-cadherin, and increased protein level of N-cadherin and vimentin, including increased migratory and invasive properties of human cancer cells. In addition, siRNA targeting of Zeb1 or Snail effectively attenuated UHRF1 deficiency-induced EMT, but siRNA targeting of Slug did not, indicating that Zeb1 and Snail play key roles in this event. Moreover, downregulation of UHRF1 induced the expression of CXCR4 in HepG2 cells. siRNA targeting of CXCR4 greatly suppressed the UHRF1 deficiency-induced EMT, as evidenced by a reversal of expression patterns of Snail and Zeb1, and by reduced migratory and invasive properties of HepG2 cells. In conclusion, our results demonstrate that downregulation of UHRF1 contributes to the induction of EMT in human cancer cells via the activation of CXCR4 signaling pathway. Our observation also suggests that UHRF1 may play a pivotal role in suppressing the malignant alteration of cancer cells.

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

“…To validate our previous report 25 , we investigated whether UHRF1 deficiency is associated with the acquisition of mesenchymal characteristics in hepatocellular carcinoma cells. In this regard, we performed western blot analysis to compare the basal levels of UHRF1 and the mesenchymal marker vimentin in HepG2, Hep3B and Huh7 cells with that in normal human fetal hepatocytes (HFHs).…”

“…We previously reported that UHRF1 deficiency upregulates CXCR4, thereby leading to EMT 25 . In this study, we confirmed an increase in the mRNA expression of CXCR4 in UHRF1-deficient HepG2 cells (Fig.…”

“…Previously, we found that the downregulation of UHRF1 leads to the induction of EMT via CXCR4 in human cancer cells 25 . In this current study, we further investigated the signaling mechanisms underlying the role of UHRF1 deficiency in EMT associated with tumor malignancy.…”

Elevated UHRF1 expression contributes to poor prognosis by promoting cell proliferation and metastasis in hepatocellular carcinoma

“…Previous study indicated that UHRF1 is overexpressed in a variety of tumor tissues such as gastric cancer, bladder cancer and HCC, and UHRF1 overexpression is negatively correlated with prognosis of HCC patients [21–26]. Additionally, the proliferative and invasive abilities of tumor cells were significantly inhibited after UHRF1 knockdown, while opposite results were obtained when UHRF1 was upregulated [27–29]. Furthermore, studies have shown that UHRF1 is regulated by microRNAs, and mTOR inhibitors showed an antitumor effect by downregulating UHRF1 [30, 31].…”

Identification of UHRF2 as a Negative Regulator of Epithelial-Mesenchymal Transition and Its Clinical Significance in Esophageal Squamous Cell Carcinoma

“…UHRF1 is a well-known epigenetic regulator. Recently, Liu et al [25] demonstrated that UHRF1 promotes EMT via the suppression of retinoblastoma 1 in human osteosarcoma cell lines, while Jung et al [26] reported that the downregulation of UHRF1 promotes EMT through the activation of the CXCR4-signaling pathway in hepatocellular carcinoma, breast cancer, and colon cancer cells. Although the precise role of UHRF1 in the EMT process has not been fully elucidated, recent reports on the UHRF family in epithelial malignant cells support our findings that UHRF2 negatively regulates EMT because of structural similarities between UHRF1 and UHRF2, followed by a potential functional conservation such as the maintenance of DNMT1-mediated DNA methylation [13, 27].…”