title: Role of phosphorylated histone H3 serine 10 in DEN-induced deregulation of Pol III genes and cell proliferation and transformation.
abstract: The products of Pol III genes (RNA polymerase III-dependent genes), such as tRNAs and 5S rRNA, are elevated in both transformed and tumor cells suggesting that they play a crucial role in tumorigenesis. An increase in Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB, augments Pol III gene transcription and is sufficient for cell transformation and tumor formation. We have demonstrated that enhancement of Brf1 and Pol III gene expression is associated with the occurrences of hepatocellular carcinoma (HCC) in mice. This suggests that Brf1 may be a key molecule during HCC development. Diethylnitrosamine (DEN), a chemical carcinogen, has been used to induce HCC in rodents. To determine the role of Brf1 and the epigenetic-regulating events in cell proliferation and transformation, hepatocytes were treated with DEN. The results indicate that DEN increases proliferation and transformation of AML-12 cells. DEN enhanced Brf1 expression and tRNA(Leu) and 5S rRNA transcription, as well as H3S10ph (phosphorylation of histone H3 serine 10). Interestingly, DEN-induced Pol III gene transcription and H3S10ph in tumor cells of liver are significantly higher than in non-tumor cells. Inhibition of H3S10ph by H3S10A attenuates the induction of Brf1 and Pol III genes. Further analysis indicates that H3S10ph occupies the promoters of Brf1 and Pol III genes to modulate their expression. Blocking H3S10ph represses cell proliferation and transformation. These results demonstrate that DEN induces H3S10ph, which mediate Brf1 expression, including but not limited Brf1-dependent genes, to upregulate Pol III gene transcription, resulting in an increase in cell proliferation and transformation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 605, Los Angeles, CA 90033, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhong
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhong
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D051817:Butyrate Response Factor 1; D002448:Cell Adhesion; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012320:RNA Polymerase III / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000477:Alkylating Agents; D051817:Butyrate Response Factor 1; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C488431:Zfp36l1 protein, mouse; D004052:Diethylnitrosamine; D012694:Serine; D012320:RNA Polymerase III