title: Abnormal expression of the ERG transcription factor in prostate cancer cells activates osteopontin.
abstract: Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5' untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2:ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases.
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille, Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Flajollet
authors.forename: Tian V
authors.initials: TV
authors.lastname: Tian
authors.forename: Anne
authors.initials: A
authors.lastname: Flourens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Tomavo
authors.forename: Arnauld
authors.initials: A
authors.lastname: Villers
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.forename: Xavier
authors.initials: X
authors.lastname: Leroy
authors.forename: Martine
authors.initials: M
authors.lastname: Duterque-Coquillaud
mesh_terms: D000368:Aged; D001665:Binding Sites; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D053495:Osteopontin