中科院上海生科院生化与细胞所宋建国研究组研究发现组蛋白去乙酰化酶1（Histone deacetylase 1，HDAC1）在转化生长因子-β1 (TGF-β1) 诱导的上皮细胞向间质细胞的转变（Epithelial-Mesenchymal Transition，EMT）过程中发挥重要作用。相关结果发表在Int J Biochem Cell Biol杂志上。
组蛋白去乙酰化酶是一类能够催化组蛋白以及其它一些蛋白的赖氨酸残基去乙酰化的酶，可以改变基因的转录状态以及信号转导，调控相应的生物事件。目前已经报道哺乳动物体内的HDACs有18种。其中，HDAC1在多种生理和病理过程中发挥了重要的作用，HDAC1能否调控肝细胞的EMT过程尚未有报道。
该研究发现：HDACs的3种结构完全不同的抑制剂均能抑制TGF-β1诱导的小鼠肝细胞的EMT；过表达HDAC1显性失活突变体或者利用RNA干扰技术降低细胞内HDAC1（HDAC1 RNAi）的水平亦可抑制TGF-β1诱导的小鼠肝细胞EMT。 HDAC抑制剂TSA（trichostatin A）以及HDAC1 RNAi也能够抑制TGF-β1诱导的细胞迁移。研究还表明，HDAC1可通过抑制ZO-1以及 E-cadherin 的启动子活性来调节TGF-β1诱导的EMT。此外，还观察到：HDAC1在多种浸润性肝癌中有较高的表达。本研究有助于加深对TGF-β1诱导的EMT的机制的深入了解，并具有潜在的相关的医学临床应用参考价值。
该研究项目得到了国家自然科学基金委、国家科技部及上海市科委的经费资助。(生物谷Bioon.net)
生物谷推荐原文出处：
The International Journal of Biochemistry & Cell Biology doi:10.1016/j.biocel.2010.05.006
Histone deacetylase 1 is required for transforming growth factor-β1-induced epithelial–mesenchymal transition
Weiwei Leia, Kehua Zhanga, Xinchao Pana, Ying Hua, Dongmei Wanga, Xinwang Yuana, Guangwen Shua and Jianguo Song, a,
a Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China
Epithelial–mesenchymal transition (EMT) has been implicated in embryonic development, fibrosis, and tumor metastasis. Histone deacetylases (HDACs) also play important roles in the control of various physiological and pathological events. However, whether HDACs are involved in the control of EMT in liver cells remains unidentified. Three structurally unrelated HDAC inhibitors completely suppress transforming growth factor-β1 (TGF-β1)-induced EMT in AML-12 murine hepatocytes and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 but not HDAC2 or downregulation of HDAC1 but not HDAC2 by RNAi suppressed TGF-β1-induced EMT. In addition, both HDAC inhibitor TSA and HDAC1 RNAi blocked cell migration. Overexpression of HDAC1 in invasive hepatocellular carcinoma (HCC) samples was detected. Further study showed that the mRNA levels of ZO-1 and E-cadherin were downregulated during TGF-β1-induced EMT, and HDAC1 can downregulate the promoter activities of ZO-1 and E-cadherin. Conclusions: our results demonstrate that HDAC1 is required for TGF-β1-induced EMT and cell migration in hepatocytes. Its high expression levels in majority of invasive HCC samples suggest that, by promoting EMT, HDAC1 can be related with the invasiveness of HCC. The data also suggest that the repression of transcription of ZO-1 and E-cadherin by HDAC1 may be involved in TGF-β1-induced EMT.
