PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin
PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin
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DOI：
10.1038/onc.2013.496
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发表时间：
2014-12-04
期刊：
影响因子：
8
通讯作者：
Gaston, K.
中科院分区：
文献类型：
--
作者：
Kershaw, R. M.;Siddiqui, Y. H.;Gaston, K.
PRH/HHEX(富含Pro的同源结构域蛋白)是一种转录因子，控制着多种组织中的细胞增殖和细胞分化。PRH的亚细胞定位异常与乳腺癌和甲状腺癌有关。此外，在急变期慢性髓系白血病和急性髓系白血病的亚群中，PRH异常定位，其活性被下调。在这里，我们发现PRH参与了细胞迁移和癌细胞侵袭的调节。我们首次发现PRH在前列腺细胞中表达，并且PRH蛋白水平的降低增加了正常前列腺上皮细胞的迁移。我们发现PRH蛋白水平的降低也增加了正常乳腺上皮细胞的迁移。反之，PRH过表达可抑制PC3、DU145前列腺癌和MDA-MB-231乳腺癌细胞的细胞迁移和侵袭。以前的工作已经表明，转化生长因子-b联合受体endoglin可以抑制前列腺癌和乳腺癌细胞的迁移。在这里，我们展示了PRH可以与永生化的前列腺和乳腺细胞中的endoglin启动子结合。在这些细胞中，PRH过表达导致endoglin蛋白表达增加，而PrH基因敲除导致endoglin蛋白表达减少。此外，我们还证明了过表达endoglin可以抑制PRH基因敲除细胞所表现出的迁移增加。我们的数据表明，PRH至少部分地通过对endoglin的直接转录调控来控制多种上皮细胞系的迁移。我们根据PRH在正常细胞中的功能以及在多种癌细胞类型中看到的PRH的错位来讨论这些结果。
PRH/HHex (proline-rich homeodomain protein) is a transcription factor that controls cell proliferation and cell differentiation in a variety of tissues. Aberrant subcellular localisation of PRH is associated with breast cancer and thyroid cancer. Further, in blast crisis chronic myeloid leukaemia, and a subset of acute myeloid leukaemias, PRH is aberrantly localised and its activity is downregulated. Here we show that PRH is involved in the regulation of cell migration and cancer cell invasion. We show for the first time that PRH is expressed in prostate cells and that a decrease in PRH protein levels increases the migration of normal prostate epithelial cells. We show that a decrease in PRH protein levels also increases the migration of normal breast epithelial cells. Conversely, PRH overexpression inhibits cell migration and cell invasion by PC3 and DU145 prostate cancer cells and MDA-MB-231 breast cancer cells. Previous work has shown that the transforming growth factor-b co-receptor Endoglin inhibits the migration of prostate and breast cancer cells. Here we show that PRH can bind to the Endoglin promoter in immortalised prostate and breast cells. PRH overexpression in these cells results in increased Endoglin protein expression, whereas PRH knockdown results in decreased Endoglin protein expression. Moreover, we demonstrate that Endoglin overexpression abrogates the increased migration shown by PRH knockdown cells. Our data suggest that PRH controls the migration of multiple epithelial cell lineages in part at least through the direct transcriptional regulation of Endoglin. We discuss these results in terms of the functions of PRH in normal cells and the mislocalisation of PRH seen in multiple cancer cell types.