title: The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer.
abstract: 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.
authors.affiliation: Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62794, USA.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhan
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Pai
authors.forename: Misako
authors.initials: M
authors.lastname: Watabe
authors.forename: Megumi
authors.initials: M
authors.lastname: Iiizumi
authors.forename: Eiji
authors.initials: E
authors.lastname: Furuta
authors.forename: Sonia
authors.initials: S
authors.lastname: Mohinta
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hirota
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Hosobe
authors.forename: Taisei
authors.initials: T
authors.lastname: Tsukada
authors.forename: Kunio
authors.initials: K
authors.lastname: Miura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takano
authors.forename: Ken
authors.initials: K
authors.lastname: Saito
authors.forename: Therese
authors.initials: T
authors.lastname: Commes
authors.forename: David
authors.initials: D
authors.lastname: Piquemal
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: 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
chemical_list: D051700:Activating Transcription Factor 3; C078418:developmentally regulated GTP-binding protein; D019204:GTP-Binding Proteins