RT Journal Article
SR Electronic
T1 PDK4-deficiency results in expedited cellular proliferation through E2F1-mediated increase of cyclins
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.106757
DO 10.1124/mol.116.106757
A1 Jonathan P Choiniere
A1 Jianguo Wu
A1 Li Wang
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/12/21/mol.116.106757.abstract
AB 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. The aim of this study was to identify potential new tumor suppressors and examine their function as cell cycle modulators and investigate their impact on the cyclin family of proteins and cyclin dependent kinases. In this study the pyruvate dehydrogenase kinase 4 (PDK4) 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 cyclin dependent kinases (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 shRNAs in HCC cells significantly decreased CYCLIN E1, A2, and E2F1 proteins. In contrast, inhibition of PDK4 activity in HCC cells increased CYCLIN E1, A2, and E2F1 proteins. These findings demonstrate that PDK4 is a critical regulator of hepatocyte proliferation via E2F1-mediated regulation of cyclins.