HDAC1 promotes liver proliferation in young mice via interactions with C/EBPbeta.
HDAC1 (histone deacetylase 1) regulates a number of biological processes in cells. Our previous studies revealed that HDAC1 inhibits proliferation of the livers in old mice. We have surprisingly observed that HDAC1 is also increased in young livers proliferating after partial hepatectomy (PH) and in human liver tumors. Increased levels of HDAC1 after PH lead to its interaction with a member of the C/EBP family, C/EBPbeta, which is also elevated after PH. At early time points after PH, the HDAC1-C/EBPbeta complex binds to the C/EBPalpha promoter and represses expression of C/EBPalpha. A detailed analysis of the role of HDAC1 and C/EBPbeta proteins in the regulation of C/EBPalpha promoter showed that, whereas C/EBPbeta alone activates the promoter, HDAC1 represses the promoter in a C/EBPbeta-dependent manner. The inhibition of HDAC1 in the livers of young mice inhibits liver proliferation after PH, which is associated with high levels of C/EBPalpha. Consistent with the positive role of HDAC1-C/EBPbeta complexes in liver proliferation, we have found that the CUGBP1-HDAC1-C/EBPbeta pathway is activated in human tumor liver samples, suggesting that HDAC1-C/EBPbeta complexes are involved in the development of liver tumors. The causal role of the CUGBP1-HDAC1 pathway in liver proliferation was examined in CUGBP1 transgenic mice, which display high levels of the CUGBP1-eIF2 complex. We have demonstrated that elevation of the HDAC1-C/EBPbeta complexes in CUGBP1 transgenic mice reduces expression of C/EBPalpha and increases the rate of liver proliferation. Thus, these studies have identified a new pathway that promotes liver proliferation in young mice and might contribute to the malignant transformations in the liver.
Wang
Guo-Li
GL
Huffington Center on Aging and Department of Pathology, Department of Medicine, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Salisbury
Elizabeth
E
Shi
Xiurong
X
Timchenko
Lubov
L
Medrano
Estela E
EE
Timchenko
Nikolai A
NA
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D000067879:CELF1 Protein; D049109:Cell Proliferation; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008110:Liver Extracts / Q000378:metabolism; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D022782:CCAAT-Enhancer-Binding Protein-beta; D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D008110:Liver Extracts; D016601:RNA-Binding Proteins; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases