Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Int J Biochem Cell Biol. 2010 Sep;42(9):1489-97. doi: 10.1016/j.biocel.2010.05.006. Epub 2010 May 16.
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-beta1 (TGF-beta1)-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-beta1-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-beta1-induced EMT, and HDAC1 can downregulate the promoter activities of ZO-1 and E-cadherin.
our results demonstrate that HDAC1 is required for TGF-beta1-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-beta1-induced EMT.
上皮-间充质转化（EMT）已被牵涉到胚胎发育、纤维化和肿瘤转移中。组蛋白去乙酰化酶（HDACs）也在控制各种生理和病理事件中发挥着重要作用。然而，HDACs 是否参与调控肝细胞中的 EMT 仍然未知。三种结构上不相关的 HDAC 抑制剂可完全抑制转化生长因子-β1（TGF-β1）诱导的 AML-12 鼠肝细胞和原代鼠肝细胞 EMT。HDAC1 的显性负突变体的表达而非 HDAC2 的表达，或通过 RNAi 下调 HDAC1 而非 HDAC2 的表达，均可抑制 TGF-β1 诱导的 EMT。此外，HDAC 抑制剂 TSA 和 HDAC1 RNAi 均可阻断细胞迁移。在侵袭性肝细胞癌（HCC）样本中检测到 HDAC1 的过表达。进一步的研究表明，在 TGF-β1 诱导的 EMT 过程中 ZO-1 和 E-钙黏蛋白的 mRNA 水平下调，而 HDAC1 可下调 ZO-1 和 E-钙黏蛋白的启动子活性。
我们的结果表明，HDAC1 是 TGF-β1 诱导的肝细胞 EMT 和细胞迁移所必需的。其在大多数侵袭性 HCC 样本中的高表达水平表明，通过促进 EMT，HDAC1 可能与 HCC 的侵袭性有关。数据还表明，HDAC1 对 ZO-1 和 E-钙黏蛋白转录的抑制可能参与了 TGF-β1 诱导的 EMT。
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