title: 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.
abstract: 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 β 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 β-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/EBPβ and HDAC1, resulting in an increase of C/EBPβ-HDAC1 complexes at later stages of liver cancer. We found that C/EBPβ-HDAC1 complexes repress promoters of three key regulators of liver functions: p53, SIRT1, and PGC1α. As the result of this suppression, the p53-, SIRT1-, and PGC1α-dependent downstream pathways are reduced, leading to increased liver proliferation. We also found that the proper regulation of C/EBPβ-HDAC1 complexes is required for the maintenance of biological levels of p53, SIRT1, and PGC1α 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/EBPβ-HDAC1 complexes on the levels of transcription, translation, and posttranslational modifications.
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jingling
authors.initials: J
authors.lastname: Jin
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Polina
authors.initials: P
authors.lastname: Iakova
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Kyle
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Emily
authors.initials: E
authors.lastname: Sullivan
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Nicole
authors.initials: N
authors.lastname: Jawanmardi
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Donehower
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Lubov
authors.initials: L
authors.lastname: Timchenko
authors.affiliation: Huffington Center on Aging and Department of Huffington Center on Aging and Departments of Pathology and Immunology, Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 77030. Electronic address: nikolait@bcm.tmc.edu.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D049109:Cell Proliferation; D004052:Diethylnitrosamine / Q000494:pharmacology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C495901:TP53 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: C/EBP; Cancer; Cancer Tumor Promoter; Cell Proliferation; Chromatin Immunoprecipitation (ChIP); Cyclin-dependent Kinase (CDK); Epigenetic; Liver; Translation
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