The transcription factor EGR-1 suppresses transformation of human fibrosarcoma HT1080 cells by coordinated induction of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1

Re-expression of EGR-1 in fibrosarcoma HT1080 suppresses transformation inc luding tumorigenicity (Huang, R-P., Liu, C., Fan, Y., Mercola, D., and Adam son, E. (1995) Cancer Res. 55, 5054-5062) owing in part to up-regulation of the transforming growth factor (TGF)-beta 1 promoter by EGR-1 which suppre sses growth by an autocrine mechanism (Liu, C., Adamson, E., and Mercola, D . (1996) Proc. Natl. Acad. Sci U. S. A. 93, 11831-11836), Here we show that enhanced cell attachment contributes to the suppression via increased secr etion of fibronectin (FN) and also of plasminogen activator inhibitor-1 (PA I-1), The secretion of FN and PAI-1 is strongly correlated with EGR-1 expre ssion (R-PEARSON = 0.971 and 0.985, respectively). Addition of authentic TG F-beta 1 to parental cells greatly stimulated secretion of PAI-1 but not FN , whereas addition of TGF-P antibody or lipofection with specific antisense TGF-PI oligonucleotides to EGR-1-regulated cells completely inhibits the s ecretion of PAI-1 but not FN, However, in gel mobility shift assays pure EG R-1 or nuclear extracts of EGR-1-regulated cells specifically bind to two G C-rich elements of the human FN promoter at positions -75/-52 and -4/+18, i ndicating that the increased secretion of FN is likely due to direct up-reg ulation by EGR-1, Moreover, adhesion was greatly enhanced in EGR-1-regulate d cells and was reversed by treatment with Arg-Gly-Asp (RGD) or PAI-1 antib ody indicating that the secreted proteins are functional, We conclude that EGR-1 regulates the coordinated expression of gene products important for c ell attachment ("oikis" factor) and normal growth control.