Glenisson Wendy, Castronovo Vincent, Waltregny David
Metastasis Research Laboratory, University of Liège, Belgium.
Biochim Biophys Acta. 2007 Oct;1773(10):1572-82. doi: 10.1016/j.bbamcr.2007.05.016. Epub 2007 Jun 12.
Transforming Growth Factor beta1 (TGFbeta1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGFbeta1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and histone acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGFbeta1-induced MF differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGFbeta1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGFbeta1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGFbeta1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGFss1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGFbeta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders.
转化生长因子β1（TGFβ1）是一种关键的细胞因子，可触发肌成纤维细胞（MF）分化，这一过程涉及组织愈合以及诸如纤维化和癌症等病理状况。与细胞形态改变一起，TGFβ1介导的成纤维细胞向肌成纤维细胞的分化特征性地与平滑肌α-肌动蛋白（α-SMA）的新表达相关，α-SMA是一种细胞骨架蛋白，可增强其收缩活性。几种细胞分化程序已与基因表达的表观遗传调控相关联，包括基因甲基化和组蛋白乙酰化。在此，我们试图研究组蛋白脱乙酰酶（HDAC）在TGFβ1诱导的MF分化中的作用。我们发现，TSA是I类和II类HDAC的全局抑制剂，可阻止培养的人皮肤成纤维细胞中TGFβ1介导的α-SMA转录本和蛋白质表达以及形态变化。为了鉴定参与MF分化的HDAC，在暴露于TGFβ1的成纤维细胞中研究了使用RNA干扰特异性HDAC沉默（HDAC1至HDAC8）的影响。在所测试的八种HDAC中，HDAC4、HDAC6和HDAC8表达的沉默损害了TGFβ1诱导的α-SMA表达。HDAC4沉默最有效地消除了α-SMA表达，还阻止了TGFβ1介导的形态变化。HDAC4的强制下调刺激了5'-TG-3'-相互作用因子（TGIF）和TGIF2同源蛋白的表达，这两种蛋白是TGFβ信号通路的已知内源性抑制剂，但对抑制性Smad7没有影响。总体而言，这些数据表明HDAC4是MF分化的必需表观遗传调节因子，并揭示HDAC4是治疗MF相关疾病的潜在靶点。
