Mitchell D C, Stafford L J, Li D, Bar-Eli M, Liu M
Institute of Biosciences and Technology, and Department of Molecular and Cellular Medicine, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
Oncogene. 2007 Mar 15;26(12):1739-47. doi: 10.1038/sj.onc.1209963. Epub 2006 Sep 11.
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.
转移抑制基因KiSS-1的缺失与多种癌症转移的进展密切相关。然而，KiSS-1在转移过程中缺失的机制仍不完全清楚。先前的研究表明，人类染色体6q16.3-q23上的遗传物质对正常组织中KiSS-1的表达至关重要。此外，通过微细胞介导将该染色体转移至癌组织中可使KiSS-1表达恢复并降低转移表型。在此，我们发现由人类染色体6q16.3-q23编码的Sp1共激活蛋白DRIP-130的缺失导致高恶性黑色素瘤细胞中KiSS-1启动子激活减少。Sp1和DRIP-130的共表达不仅可恢复KiSS-1的表达，还可抑制高转移性黑色素瘤细胞的侵袭和迁移行为，这与这些细胞中KiSS-1转移抑制基因的过表达相似。此外，我们证明KiSS-1的表达受KiSS-1启动子前100 bp区域内的Sp1元件调控，并且靶向缺失一个跨越-93至-58的富含GC的单一区域会中断Sp1和DRIP-130调节的KiSS-1表达的转录控制。因此，我们的结果表明DRIP-130是正常组织中KiSS-1反式激活的关键调节因子，并且由于人类染色体6q16.3-q23的大片段缺失导致DRIP-130表达缺失，从而引发肿瘤转移增加。
