Transcriptional and Translational Regulation of C/EBPβ-HDAC1 Protein Complexes Controls Different Levels of p53, SIRT1, and PGC1α Proteins at the Early and Late Stages of Liver Cancer

Cancer changes biological processes in the liver by altering gene expression at the levels of transcription, translation, and protein modification. The RNA binding protein CUGBP1 is a key regulator of translation of CCAAT enhancer binding protein beta and histone deacetylase 1 (HDAC1). These proteins form complexes that are involved in the regulation of liver biology. Here we show a critical role of the translational activation of CCAAT/enhancer binding protein beta-HDAC1 complexes in the development of liver cancer mediated by diethylnitrosamine. We found that diethylnitrosamine increases the levels of CUGBP1 and activates CUGBP1 by phosphorylation, leading to the formation of the CUGBP1-eIF2 complex, which is an activator of translation of CUGBP1-dependent mRNAs. The elevation of the CUGBP1-eIF2 complex increases translation of C/EBP beta and HDAC1, resulting in an increase of C/EBP beta-HDAC1 complexes at later stages of liver cancer. We found that C/EBP beta-HDAC1 complexes repress promoters of three key regulators of liver functions: p53, SIRT1, and PGC1 alpha. As the result of this suppression, the p53-, SIRT1-, and PGC1 alpha-dependent downstream pathways are reduced, leading to increased liver proliferation. We also found that the proper regulation of C/EBP beta-HDAC1 complexes is required for the maintenance of biological levels of p53, SIRT1, and PGC1 alpha in quiescent livers and at early stages of liver cancer. Taken together, these studies showed that the development of liver cancer includes a tight regulation of levels of C/EBP beta-HDAC1 complexes on the levels of transcription, translation, and posttranslational modifications.