Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130

D. C. Mitchell, L. J. Stafford, D. Li, M. Bar-Eli, M. Liu

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1739-1747
Number of pages9
JournalOncogene
Volume26
Issue number12
DOIs
Publication statusPublished - Mar 15 2007

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Keywords

  • CRSP3
  • Cancer metastasis
  • GPR54
  • KiSS1
  • Sp1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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