Regulation of KiSS-1 metastasis suppressor gene expression in breast cancer cells by direct interaction of transcription factors activator protein-2alpha and specificity protein-1.
KiSS-1 has been shown to function as a tumor metastasis suppressor gene and reduce the number of metastases in different cancers. The expression of KiSS-1 or KiSS1, like other tumor suppressor, is commonly reduced or completely ablated in a variety of cancers via an unknown mechanism. Here we show that the loss of KiSS-1 expression in highly metastatic breast cancer cell lines correlates directly with the expression levels of two transcription factors, activator protein-2alpha (AP-2alpha) and specificity protein 1 (Sp1), which synergistically activate the transcriptional regulation of KiSS-1 in breast cancer cells. Although the KiSS-1 promoter contains multiple AP-2alpha binding elements, AP-2alpha-mediated regulation occurs indirectly through Sp1 sites, as determined by deletion and mutation analysis. Overexpression of AP-2alpha into highly metastatic breast cell lines did not alter KiSS-1 promoter-driven luciferase gene activity. However, co-transfection of AP-2alpha wild-type or the dominant negative form of AP-2 lacking its C-terminal DNA-binding domain, AP-2B, together with Sp1, increased KiSS-1 promoter activity dramatically, suggesting that AP-2alpha regulation of KiSS-1 transcription does not require direct binding to the KiSS-1 promoter. Furthermore, we demonstrated that AP-2alpha directly interacted with Sp1 to form transcription complexes at two tandem Sp1-binding sites of the promoter to activate KiSS-1 transcription. Together, our results indicate that AP-2alpha and Sp1 are strong transcriptional regulators of KiSS-1 and that loss or decreased expression of AP-2alpha in breast cancer may account for the loss of tumor metastasis suppressor KiSS-1 expression and thus increased cancer metastasis.
Mitchell
Dianne C
DC
Institute of Biosciences and Technology, Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, Houston 77030, USA.
Abdelrahim
Maen
M
Weng
Jinsheng
J
Stafford
Lewis J
LJ
Safe
Stephen
S
Bar-Eli
Menashe
M
Liu
Mingyao
M
D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000556:secondary*; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D059648:Kisspeptins; D011401:Promoter Regions, Genetic / Q000502:physiology; D011506:Proteins / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D025521:Tumor Suppressor Proteins
C106628:KISS1 protein, human; D059648:Kisspeptins; D011506:Proteins; D016329:Sp1 Transcription Factor; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins