The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer.
The tumor metastasis suppressor gene Drg-1 has been shown to suppress metastasis without affecting tumorigenicity in immunodeficient mouse models of prostate and colon cancer. Expression of Drg-1 has also been found to have a significant inverse correlation with metastasis or invasiveness in various types of human cancer. However, how Drg-1 exerts its metastasis suppressor function remains unknown. In the present study, to elucidate the mechanism of action of the Drg-1 gene, we did a microarray analysis and found that induction of Drg-1 significantly inhibited the expression of activating transcription factor (ATF) 3, a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. We also showed that Drg-1 attenuated the endogenous level of ATF3 mRNA and protein in prostate cancer cells, whereas Drg-1 small interfering RNA up-regulated the ATF3 expression. Furthermore, Drg-1 suppressed the promoter activity of the ATF3 gene, indicating that Drg-1 regulates ATF3 expression at the transcriptional level. Our immunohistochemical analysis on prostate cancer specimens revealed that nuclear expression of ATF3 was inversely correlated to Drg-1 expression and positively correlated to metastases. Consistently, we have found that ATF3 overexpression promoted invasiveness of prostate tumor cells in vitro, whereas Drg-1 suppressed the invasive ability of these cells. More importantly, overexpression of ATF3 in prostate cancer cells significantly enhanced spontaneous lung metastasis of these cells without affecting primary tumorigenicity in a severe combined immunodeficient mouse model. Taken together, our results strongly suggest that Drg-1 suppresses metastasis of prostate tumor cells, at least in part, by inhibiting the invasive ability of the cells via down-regulation of the expression of the ATF3 gene.
Bandyopadhyay
Sucharita
S
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62794, USA.
Wang
Ying
Y
Zhan
Rui
R
Pai
Sudha K
SK
Watabe
Misako
M
Iiizumi
Megumi
M
Furuta
Eiji
E
Mohinta
Sonia
S
Liu
Wen
W
Hirota
Shigeru
S
Hosobe
Sadahiro
S
Tsukada
Taisei
T
Miura
Kunio
K
Takano
Yukio
Y
Saito
Ken
K
Commes
Therese
T
Piquemal
David
D
Hai
Tsonwin
T
Watabe
Kounosuke
K
D051700:Activating Transcription Factor 3 / Q000235:genetics*; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics / Q000517:prevention & control; D010957:Plasmids; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015183:Restriction Mapping; D014162:Transfection
D051700:Activating Transcription Factor 3; C078418:developmentally regulated GTP-binding protein; D019204:GTP-Binding Proteins