Histone deacetylase 1 is required for transforming growth factor-beta1-induced epithelial-mesenchymal transition.
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.


CONCLUSIONS
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.
Lei
Weiwei
W
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Zhang
Kehua
K
Pan
Xinchao
X
Hu
Ying
Y
Wang
Dongmei
D
Yuan
Xinwang
X
Shu
Guangwen
G
Song
Jianguo
J
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008648:Mesoderm / Q000166:cytology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D056284:Histone Deacetylase 1; D002118:Calcium