Brg-1 mediates the constitutive and fenretinide-induced expression of SPARC in mammary carcinoma cells via its interaction with transcription factor Sp1.
BACKGROUND
Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular protein that mediates cell-matrix interactions. It has been shown, depending on the type of cancer, to possess either pro- or anti-tumorigenic properties. The transcriptional regulation of the SPARC gene expression has not been fully elucidated and the effects of anti-cancer drugs on this process have not been explored.


RESULTS
In the present study, we demonstrated that chromatin remodeling factor Brg-1 is recruited to the proximal SPARC promoter region (-130/-56) through an interaction with transcription factor Sp1. We identified Brg-1 as a critical regulator for the constitutive expression levels of SPARC mRNA and protein in mammary carcinoma cell lines and for SPARC secretion into culture media. Furthermore, we found that Brg-1 cooperates with Sp1 to enhance SPARC promoter activity. Interestingly, fenretinide [N-4(hydroxyphenyl) retinamide, 4-HPR], a synthetic retinoid with anti-cancer properties, was found to up-regulate the transcription, expression and secretion of SPARC via induction of the Brg-1 in a dose-dependent manner. Finally, our results demonstrated that fenretinide-induced expression of SPARC contributes significantly to a decreased invasion of mammary carcinoma cells.


CONCLUSIONS
Overall, our results reveal a novel cooperative role of Brg-1 and Sp1 in mediating the constitutive and fenretinide-induced expression of SPARC, and provide new insights for the understanding of the anti-cancer effects of fenretinide.
Xu
Yong Zhong
YZ
Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Heravi
Mitra
M
Thuraisingam
Thusanth
T
Di Marco
Sergio
S
Muanza
Thierry
T
Radzioch
Danuta
D
D000818:Animals; D001483:Base Sequence; D004247:DNA; D004265:DNA Helicases / Q000502:physiology*; D017313:Fenretinide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D015676:Osteonectin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D009687:Nuclear Proteins; D015676:Osteonectin; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D017313:Fenretinide; D004247:DNA; C513194:Smarca4 protein, mouse; D004265:DNA Helicases