ZFIN ID: ZDB-PUB-170912-5
Loss of PRP4K drives anoikis resistance in part by dysregulation of epidermal growth factor receptor endosomal trafficking
Corkery, D.P., Clarke, L.E., Gebremeskel, S., Salsman, J., Pinder, J., Le Page, C., Meunier, L., Xu, Z., Mes-Masson, A.M., Berman, J.N., Johnston, B., Dellaire, G.
Date: 2017
Source: Oncogene   37(2): 174-184 (Journal)
Registered Authors: Berman, Jason, Corkery, Dale
Keywords: none
MeSH Terms:
  • Animals
  • Anoikis/genetics*
  • Biomarkers, Tumor/deficiency
  • Biomarkers, Tumor/genetics
  • Breast Neoplasms/pathology
  • Cell Line, Tumor
  • Cell Nucleus/metabolism
  • Down-Regulation
  • Endosomes/metabolism*
  • Epidermal Growth Factor/metabolism
  • Epithelial Cells/cytology
  • Epithelial Cells/pathology
  • Female
  • Humans
  • Lung Neoplasms/pathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness/pathology
  • Ovarian Neoplasms/pathology
  • Protein-Serine-Threonine Kinases/deficiency*
  • Protein-Serine-Threonine Kinases/genetics
  • RNA, Small Interfering/metabolism
  • Ribonucleoprotein, U4-U6 Small Nuclear/deficiency*
  • Ribonucleoprotein, U4-U6 Small Nuclear/genetics
  • Signal Transduction/genetics*
  • Xenograft Model Antitumor Assays
  • Zebrafish
PubMed: 28892043 Full text @ Oncogene
Anoikis acts as a critical barrier to metastasis by inducing cell death upon cancer cell detachment from the extracellular matrix (ECM), thereby preventing tumor cell dissemination to secondary sites. The induction of anoikis requires the lysosomal-mediated downregulation of epidermal growth factor receptors (EGFRs) leading to termination of pro-survival signaling. In this study, we demonstrate that depletion of pre-mRNA splicing factor 4 kinase (PRP4K; also known as PRPF4B) causes dysregulation of EGFR trafficking and anoikis resistance. We also report a novel cytoplasmic localization of PRP4K at the late endosome, and demonstrate both nuclear and cytoplasmic localization in breast, lung and ovarian cancer tissue. Mechanistically, depletion of PRP4K leads to reduced EGFR degradation following cell detachment from the ECM and correlates with increased TrkB, vimentin and Zeb1 expression. As a result, PRP4K loss promotes sustained growth factor signaling and increased cellular resistance to anoikis in vitro and in a novel zebrafish xenotransplantation model of anoikis sensitivity, as well as increased metastasis in a mouse model of ovarian cancer. Thus, PRP4K may serve as a potential biomarker of anoikis sensitivity in ovarian and other epithelial cancers.Oncogene advance online publication, 11 September 2017; doi:10.1038/onc.2017.318.