Abstract
Loss of the metastasis suppressor gene, KiSS-1 has been strongly correlated to the progression of metastases in numerous types of cancers. The mechanism through which KiSS-1 is lost during metastasis, however, is still not completely known. Previous studies have shown that genetic material on human chromosome 6q16.3–q23 is essential for KiSS-1 expression in normal tissues. Additionally, microcell-mediated transfer of this chromosome in cancerous tissue results in rescued expression of KiSS-1 and reduced metastatic phenotype. Here, we show that loss of Sp1-coactivator protein DRIP-130, which is encoded by human chromosome 6q16.3–q23, results in reduced KiSS-1 promoter activation in highly malignant melanoma cells. Co-expression of Sp1 and DRIP-130 not only rescues KiSS-1 expression, but also induces an inhibition of the invasive and migratory behavior in highly metastatic melanoma cells, similar to the overexpression of KiSS-1 metastasis suppressor gene in those cells. Furthermore, we demonstrate that KiSS-1 expression is regulated by Sp1 elements within the first 100-bp region of the KiSS-1 promoter and that targeted deletion of a single GC-rich region spanning −93 to −58 interrupts Sp1- and DRIP-130-modulated transcriptional control of KiSS-1 expression. Our results thus suggest that DRIP-130 is a key regulator in KiSS-1 transactivation in normal tissue, and that the loss of DRIP-130 expression, as a result of the gross loss of human chromosome 6q16.3–q23, provokes increased tumor metastasis.
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Acknowledgements
This work is partially supported by a Predoctoral Traineeship Awards (W81XWH-05-1-0353 and DAMD17-03-1-0435) from DOD Breast Cancer Program to DM and LS, and by the NIH grants (5R01HL064792 and 1R01CA106479) to ML. We thank Dr Jun Qin at Baylor College of Medicine for the DRIP-130 construct.
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Mitchell, D., Stafford, L., Li, D. et al. Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130. Oncogene 26, 1739–1747 (2007). https://doi.org/10.1038/sj.onc.1209963
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DOI: https://doi.org/10.1038/sj.onc.1209963
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