title: Down-regulation of BORIS/CTCFL efficiently regulates cancer stemness and metastasis in MYCN amplified neuroblastoma cell line by modulating Wnt/β-catenin signaling pathway.
abstract: BORIS/CTCFL is a vital nucleotide binding protein expressed during embryogenesis and gametogenesis. BORIS/CTCFL is the paralogue of transcriptional repressor protein CTCF, which is aberrantly expressed in various malignancies and primarily re-expressed in cancer stem cells (CSCs). The mechanism behind regulation of BORIS in various cancer conditions and tumor metastases is so far not explored in detail. The aim of the study was to understand the influence of BORIS/CTCFL on stemness and metastasis by regulating well-known oncogenes and related signaling pathways. In our study, we have identified a cross-talk between expression of BORIS/CTCFL and Wnt/β-catenin signaling pathway, which plays a crucial role in various processes including ontogenesis, embryogenesis and maintenance of stem cell properties. Upon knockdown of BORIS/CTCFL, we observed an upregulation of Mesenchymal to Epithelial transition markers such as E-cad and downregulation of Epithelial to Mesenchymal transition markers such as N-CAD, Vimentin, SNAIL, etc. This transition was accomplished by activation of Wnt/β-catenin signaling pathway by regulating upstream and downstream Wnt associated proteins including β-catenin, Wnt3a/5a, CD44, MYC etc. We also identified that BMI1, an oncogene belonging to polycomb group expressed positively with levels of BORIS/CTCFL. Our study implicates the role of BORIS/CTCFL in maintenance of stemness and in transition from mesenchymal to epithelial state in MYC amplified neuroblastoma IMR-32 cells. Effectively controlling BORIS/CTCFL levels can inhibit disease establishment and hence can be considered as a potent target for cancer therapy.
authors.affiliation: Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Training and Development Complex, CSIR Campus, CSIR Road, Taramani, Chennai, India.
authors.forename: Koteswara Rao
authors.initials: KR
authors.lastname: Garikapati
authors.affiliation: Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Nibedita
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Venkata Krishna Kanth
authors.initials: VKK
authors.lastname: Makani
authors.affiliation: Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Cilamkoti
authors.affiliation: Functional Genomics and Gene Silencing Group, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Utpal
authors.initials: U
authors.lastname: Bhadra
authors.affiliation: Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India. Electronic address: manikapb@gmail.com.
authors.forename: Manika Pal
authors.initials: MP
authors.lastname: Bhadra
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000502:physiology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D051153:Wnt Proteins; D051176:beta Catenin
keywords: BORIS/CTCFL; Cancer stemness; Metastasis and EMT/MET; Wnt/β-catenin signaling