Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes.
In the majority of aggressive tumorigenic prostate cancer cells, the transcription factor Egr1 is overexpressed. We provide new insights of Egr1 involvement in proliferation and survival of TRAMP C2 prostate cancer cells by the identification of several new target genes controlling growth, cell cycle progression, and apoptosis such as cyclin D2, P19ink4d, and Fas. Egr1 regulation of these genes, identified by Affymetrix microarray, was confirmed by real-time PCR, immunoblot, and chromatin immunoprecipitation assays. Furthermore we also showed that Egr1 is responsible for cyclin D2 overexpression in tumorigenic DU145 human prostate cells. The regulation of these genes by Egr1 was demonstrated using Egr1 antisense oligonucleotides that further implicated Egr1 in resistance to apoptotic signals. One mechanism was illustrated by the ability of Egr1 to inhibit CD95 (Fas/Apo) expression, leading to insensitivity to FasL. The results provide a mechanistic basis for the oncogenic role of Egr1 in TRAMP C2 prostate cancer cells.
Virolle
Thierry
T
Burnham Institute, La Jolla Cancer Research Center, La Jolla, California 92037, USA.
Krones-Herzig
Anja
A
Baron
Veronique
V
De Gregorio
Giorgia
G
Adamson
Eileen D
ED
Mercola
Dan
D
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D056742:Cyclin D2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D017874:Immediate-Early Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C486196:Ccnd2 protein, mouse; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016213:Cyclins; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D017874:Immediate-Early Proteins; C499479:Mad protein, mouse; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D012097:Repressor Proteins; D014157:Transcription Factors; D019014:fas Receptor