Programs in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Lab Invest. 2010 Feb;90(2):222-33. doi: 10.1038/labinvest.2009.128. Epub 2009 Nov 30.
Previously we described that bone morphogenetic protein-7 (BMP7) could protect prostate cancer C4-2B cells from serum starvation-induced apoptosis via survivin induction. Here, for the first time, we identify Runx2 as a key regulator of survivin transcription. In C4-2B cells grown normally, suppression of Runx2 reduced survivin expression. Using ChIP assays, two regions of the survivin promoter, -1953 to -1812 (I) and -1485 to -1119 (II) encompassing consensus Runx-binding sites were examined. Runx2 was found to be associated with both regions, with a stronger affinity to region-I. In serum-starved cells neither region was occupied, but BMP7 restored association to region-II and not region-I. In reporter assays, transcription activity by BMP7 was significantly reduced when sequences including binding sites of region-II were deleted. Additionally, Runx2 expression was enhanced by BMP7 in these cells. Along with a strong survivin expression, a trend in increased Runx2 expression in human prostate cancer cells and tissues was noted. In the conditional Pten-knockout mouse, Runx2 level increased with growth of prostate tumor. The data define a novel role of Runx2 in regulating survivin expression in malignant epithelial cells and identify it as a critical factor in BMP signaling that protects cancer cells against apoptosis.
先前我们曾描述过骨形态发生蛋白-7（BMP7）可通过诱导生存素来保护前列腺癌细胞 C4-2B 免受血清饥饿诱导的凋亡。在这里，我们首次确定 Runx2 是生存素转录的关键调节因子。在正常生长的 C4-2B 细胞中，抑制 Runx2 会降低生存素的表达。通过 ChIP 分析，我们检测了生存素启动子的两个区域，-1953 到-1812（I）和-1485 到-1119（II），这两个区域包含了公认的 Runx 结合位点。发现 Runx2 与这两个区域都有关联，与区域-I 的亲和力更强。在血清饥饿的细胞中，两个区域都没有被占据，但 BMP7 恢复了与区域-II 的结合，而不是区域-I。在报告基因实验中，当包括区域-II 结合位点的序列缺失时，BMP7 的转录活性显著降低。此外，在这些细胞中，BMP7 增强了 Runx2 的表达。除了强烈的生存素表达外，还注意到人类前列腺癌细胞和组织中的 Runx2 表达增加。在条件性 Pten 敲除小鼠中，随着前列腺肿瘤的生长，Runx2 水平增加。这些数据定义了 Runx2 在调节恶性上皮细胞中生存素表达的新作用，并将其确定为 BMP 信号通路中保护癌细胞免受凋亡的关键因素。
