Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer.
Deregulated expression of ETS transcription factors has emerged as an important event in prostate cancer pathogenesis. Here we show that the expression of epithelial-specific ETS (ESE)-3 factor is frequently reduced at the RNA and protein level in prostate cancer clinical samples compared to normal prostate. In PC3 and DU145 cells, ESE-3 was silenced by methylation of an evolutionarily conserved CpG site in its promoter and treatment with 5-aza-2'-deoxycytidine restored its expression. In a prostate epithelial cell transformation model, methylation of this site was inversely correlated with ESE-3 expression and occurred only in Ras-transformed and tumorigenic cells and not in normal and immortalized cells suggesting that ESE-3 silencing was functionally linked to oncogenic transformation. Consistent with a tumor suppressor function, re-expression of ESE-3 in prostate cancer cells inhibited clonogenic survival and induced apoptotic cell death. ESE-3 increased the level of procaspase-3, a key element in the apoptotic cascade. This effect was mediated at the transcriptional level by direct binding of ESE-3 to the caspase-3 promoter. Collectively, our findings implicate ESE-3 as a candidate tumor suppressor in prostate cancer. Decreased expression of ESE-3 may result in loss of important regulatory mechanisms in prostate epithelial cells and contribute to the pathogenesis of prostate cancer.
Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
R
R
Cangemi
A
A
Mensah
V
V
Albertini
A
A
Jain
M
M
Mello-Grand
G
G
Chiorino
C V
CV
Catapano
G M
GM
Carbone
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C403306:EHF protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins