HDAC1 Cooperates with C/EBPα in the Inhibition of Liver Proliferation in Old Mice

Abstract

Epigenetic control of liver proliferation involves cooperation between transcription factors and chromatin-remodeling proteins. In this work, we found that the levels of HDAC1 (histone deacetylase 1) are increased in quiescent livers of old mice. The elevation of HDAC1 in liver is mediated by the RNA-binding protein CUGBP1. We found that the age-associated CUGBP1-eIF2 complex binds to the 5 region of HDAC1 mRNA and increases translation of HDAC1 in the liver. Further analyses showed that CUGBP1 also increases expression of HDAC1 in cultured cells, in the livers of CUGBP1 transgenic mice, and in the livers of mice injected with cyclin D3, which enhances the formation of the CUGBP1-eIF2 complex. In livers of old mice, HDAC1 interacts with the transcription factor C/EBP␣ and is recruited by this protein to E2F-dependent promoters as a component of high M r C/EBP␣-Brm complexes. The recruitment of HDAC1 to c-Myc and FoxM1B promoters leads to deacetylation of histone H3 at Lys-9 on these E2F-dependent promoters. We show that HDAC1 is an important mediator of growth-inhibitory activity of C/EBP␣ and that small interfering RNA-mediated inhibition of HDAC1 reduces the ability of C/EBP␣ to inhibit cell proliferation. In addition, we have found that both elevation of HDAC1 and interaction of C/EBP␣ with HDAC1 are controlled by cyclin D3-dependent mechanisms. Treatment of old mice with growth hormone, which reduces cyclin D3 levels, leads to the reduction of the CUGBP1-eIF2 complex, normalization of HDAC1 levels, and inhibition of interactions of HDAC1 with C/EBP␣-Brm complexes. Thus, our data demonstrate that translational elevation of HDAC1 in livers of old mice is involved in the assembly of high M r protein-protein complexes that inhibit liver proliferation.Although the liver is a quiescent tissue, it is able to completely regenerate itself in response to injury and after partial hepatectomy. It has been shown that aging significantly reduces regenerative capacities of the liver and proliferative response after partial hepatectomy (1-3). The first fundamental work was performed by Bucher et al.(1) in 1964 and showed that old animals have a delayed and reduced peak of DNA synthesis. This phenomenon was later confirmed by a number of publications from other groups (2-5). Despite intensive work, very little is known about biochemical pathways by which aging inhibits liver proliferation. Recent studies revealed that expression and activities of two transcription factors, C/EBP␣ and FoxM1B, are altered in livers of old mice (4 -7). The C/EBP family member C/EBP␣ is expressed at high levels in the liver and is involved in the regulation of liver growth and differentiation (8 -10). C/EBP␣ inhibits liver proliferation in young mice through the interactions with Cdk2 and p21, leading to the inhibition of Cdk2 kinase activity (11-13). In old livers, C/EBP␣ is recruited to Brm complexes to repress E2F targets through the occupation of E2F-dependent promoters (5, 14). FoxM1B is not detectable in quiescent livers but is elevated af...

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

“…Therefore, the S193D mice represent a powerful animal model for the investigations of the responses of livers of aged mice to drug treatments. Another member of C/EBP family, C/EBP␤, is similar to C/EBP␣ and is involved in the regulation of chromatin structure of hepatocytes through interactions with HDAC1 (16,17). It has been shown that the C/EBP␤-HDAC1 complexes are abundant in livers of old mice and repress SIRT1 (18).…”

“…The formation of C/EBP␤-HDAC1 complexes is mainly controlled by the RNA-binding protein CUGBP1 (14). CUGBP1 increases translation of HDAC1 and two isoforms of C/EBP␤: C/EBP␤-LAP and C/EBP␤-LIP (16,17,19). A truncated isoform of C/EBP␤-LIP lacks activation domains and functions as a dominant-negative molecule by inhibiting activities of fulllength C/EBP␣ and C/EBP␤ proteins (20,21).…”

Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning DNA Repair, Cell Cycle Progression and Survival in Development & Disease

“…Interactions between C/EBP and E2F also play important roles during senescence. Indeed, C/EBPα and HDAC1 are recruited to hepatic DNA from older, but not young, mice (Wang et al, 2008). Recruitment of these two factors is accompanied by decreased transcription of E2F target genes.…”

CELF1, a Multifunctional Regulator of Posttranscriptional Networks

“…CELF1-HDAC1-C/EBPbeta pathway is activated in young rat liver cells and in human tumor liver samples suggesting that CELF1-HDAC1-C/EBPbeta complexes are involved in the development of liver tumors [162], [163]. The inhibition of the ubiquitin-dependent proteasome system (UPS) via specific drugs (such as Bortezomib) is one type of approach used to combat cancer [164].…”