Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell Rep. 2013 Apr 25;3(4):1175-86. doi: 10.1016/j.celrep.2013.03.019. Epub 2013 Apr 11.
The epithelial-to-mesenchymal transition (EMT) is important for the development of cancer metastases and organ fibrosis, conditions prevalent in aging. Because sirtuins affect the pathology of aging, we tested the effect of SirT1 on EMT. Reduced SIRT1 levels in HMLER breast cancer cells led to increased metastases in nude mice, and the loss of SIRT1 in kidney tubular epithelial cells exacerbated injury-induced kidney fibrosis. SIRT1 reduces EMT in cancer and fibrosis by deacetylating Smad4 and repressing the effect of TGF-β signaling on MMP7, a Smad4 target gene. Consequently, less E-cadherin is cleaved from the cell surface and β-catenin remains bound to E-cadherin at the cell-cell junctions. Our findings suggest that the SIRT1/Smad4/β-catenin axis may be a target for diseases driven by EMT.
上皮-间充质转化（EMT）对于癌症转移和器官纤维化的发展很重要，这些情况在衰老中很普遍。由于沉默信息调节因子 2 相关酶 1（sirtuins）会影响衰老的病理，我们测试了 SirT1 对 EMT 的影响。在 HMLER 乳腺癌细胞中降低 SIRT1 水平会导致裸鼠转移增加，而肾脏管状上皮细胞中 SIRT1 的缺失会加剧损伤诱导的肾脏纤维化。SIRT1 通过去乙酰化 Smad4 并抑制 TGF-β 信号对 MMP7（Smad4 的靶基因）的作用来减少癌症和纤维化中的 EMT。因此，更少的 E-钙黏蛋白从细胞表面被切割，β-连环蛋白仍与细胞-细胞连接处的 E-钙黏蛋白结合。我们的研究结果表明，SIRT1/Smad4/β-连环蛋白轴可能是 EMT 驱动疾病的靶点。
