title: 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.
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Yi-Deun
authors.initials: YD
authors.lastname: Jung
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Shim
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Seong-Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Si Ho
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Kwangmo
authors.initials: K
authors.lastname: Yang
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Heo
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
authors.forename: Moon-Taek
authors.initials: MT
authors.lastname: Park
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C527276:CXCR4 protein, human; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases