Prostate Transglutaminase (TGase-4) Induces Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells.
More men die with prostate cancer (PCa) than from it. However, once PCa is no longer organ-confined, it is associated with significant mortality. Epithelial-to-mesenchymal transition (EMT) is one mechanism facilitating progression in cancer. Our studies of transglutaminase-4 (TGase-4), a member of the TGase family, expressed in the prostate gland, have implicated it in the regulation of the invasive properties of PCa. The present study investigated the role of TGase-4 on EMT of PCa cells.



A panel of PCa cell lines: CA-HPV-10, PZ-HPV-7, PC-3 and DU-145 were used. An anti-TGase-4 transgene was constructed to eliminate the expression of TGase-4 in CA-HPV-10 (positive for TGase-4). An expression construct for human TGase-4 was used to transfect PCa cells negative for TGase-4. The pattern of E-cadherin, N-cadherin and vimentin in these cells were evaluated using immunofluorescent staining. Cell motility was assessed using scratch wounding and ekectric cell-substrate impedance sensing (ECIS) assays.



Treatment of PZ-HPV-7 and CA-HPV-10 cells with rhTGase-4 resulted in a significant increase in cell migration (1,407.9 Ω±6.4 Ω vs. 1,691.2 Ω±8.3 Ω in non-treated and rhTGase-4 treated cells, respectively, p<0.01). Cells strongly expressing E-cadherin showed substantial changes of E-cadherin staining in that, after treatment with TGase-4, the intercellular staining of E-cadherin was diminished. Concomitantly, there was acquisition of N-cadherin in TGase-4-treated cells. Elimination of TGase-4 from CA-HPV-10 cells significantly decreased cell motility (128.1 Ω±107.4 Ω vs. 31.7 Ω±26.2 Ω, in CA-HPV-10 control and CA-HPV-10/TGase-4 knockout cells). Knocking- out TGase-4 from CA-HPV-10 cells also resulted in substantial loss of N-cadherin in the cells.



TGase-4 resulted in loss of E-cadherin/acquisition of N-cadherin and cell migration indicating it is a keen regulator of EMT in prostate epithelia-derived cancer cells. In concert with its other properties involved in disease progression, the present observations suggest TGase-4 as a prospective marker of disease progression.
Department of Pathology, University of Arizona College of Medicine, Arizona Cancer Center and BIO5 Institute, Tucson, AZ, U.S.A ablinrj@email.arizona.edu jiangw@cf.ac.uk.
Richard J
RJ
Ablin
Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K.
Sioned
S
Owen
Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K. ablinrj@email.arizona.edu jiangw@cf.ac.uk.
Wen G
WG
Jiang
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019076:Transgenes; D011503:Transglutaminases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
C418702:transglutaminase 4; D011503:Transglutaminases
EMT; Prostate transglutaminase; cadherin switch; cell migration; epithelial–mesenchymal transition; prostate cancer