title: Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins.
abstract: Hepatocellular carcinoma (HCC) is a common form of cancer with prevalence worldwide. There are many factors that lead to the development and progression of HCC. This study aimed to identify potential new tumor suppressors, examine their function as cell cycle modulators, and investigate their impact on the cyclin family of proteins and cyclin-dependent kinases (CDKs). In this study, the pyruvate dehydrogenase kinase (PDK)4 gene was shown to have potential tumor suppressor characteristics. PDK4 expression was significantly downregulated in human HCC. Pdk4-/-mouse liver exhibited a consistent increase in cell cycle regulator proteins, including cyclin D1, cyclin E1, cyclin A2, some associated CDKs, and transcription factor E2F1. PDK4-knockdown HCC cells also progressed faster through the cell cycle, which concurrently expressed high levels of cyclins and E2F1 as seen in the Pdk4-/-mice. Interestingly, the induced cyclin E1 and cyclin A2 caused by Pdk4 deficiency was repressed by arsenic treatment in mouse liver and in HCC cells. E2f1 deficiency in E2f1-/-mouse liver or knockdown E2F1 using small hairpin RNAs in HCC cells significantly decreased cyclin E1, cyclin A2, and E2F1 proteins. In contrast, inhibition of PDK4 activity in HCC cells increased cyclin E1, cyclin A2, and E2F1 proteins. These findings demonstrate that PDK4 is a critical regulator of hepatocyte proliferation via E2F1-mediated regulation of cyclins.
authors.affiliation: Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut (J.C., J.W., L.W.); Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut (L.W.); Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut (L.W.); and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (L.W.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Choiniere
authors.affiliation: Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut (J.C., J.W., L.W.); Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut (L.W.); Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut (L.W.); and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (L.W.).
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut (J.C., J.W., L.W.); Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut (L.W.); Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut (L.W.); and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China (L.W.) li.wang@uconn.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001151:Arsenic / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D016213:Cyclins / Q000378:metabolism*; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D016213:Cyclins; D050687:E2F1 Transcription Factor; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D001151:Arsenic