title: Cytoplasmic PML promotes TGF-β-associated epithelial-mesenchymal transition and invasion in prostate cancer.
abstract: Epithelial-mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Buczek
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Miles
authors.affiliation: Department of Urology, City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: W
authors.initials: W
authors.lastname: Green
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Johnson
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Boocock
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Pockley
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Rees
authors.affiliation: Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals Trust, Nottingham, UK.
authors.forename: G
authors.initials: G
authors.lastname: Hulman
authors.affiliation: Department of Histopathology, Royal Derby Hospital, Derby, UK.
authors.forename: G
authors.initials: G
authors.lastname: van Schalkwyk
authors.affiliation: Department of Urology, City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Parkinson
authors.affiliation: Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals Trust, Nottingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Hulman
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.|Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals Trust, Nottingham, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Powe
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: T
authors.initials: T
authors.lastname: Regad
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D000071156:Promyelocytic Leukemia Protein; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018160:Receptors, Cytoplasmic and Nuclear; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000097606:Exportin 1 Protein; C497782:SMAD2 protein, human; C070576:PML protein, human