Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells
Journal
Hepatology
Journal Volume
53
Journal Issue
1
Pages
148-159
Date Issued
2011
Author(s)
CHE-MING TENG
Abstract
Histone deacetylase (HDAC) inhibitors exhibit a unique ability to degrade topoisomerase (topo)IIα in hepatocellular carcinoma (HCC) cells, which contrasts with the effect of topoII-targeted drugs on topoIIβ degradation. This selective degradation might foster novel strategies for HCC treatment in light of the correlation of topoIIα overexpression with the aggressive tumor phenotype and chemoresistance. Here we report a novel pathway by which HDAC inhibitors mediate topoIIα proteolysis in HCC cells. Our data indicate that HDAC inhibitors transcriptionally activated casein kinase (CK)2α expression through increased association of acetylated histone H3 with the CK2α gene promoter. In turn, CK2 facilitated the binding of topoIIα to COP9 signalosome subunit (Csn)5 by way of topoIIα phosphorylation. Furthermore, we identified Fbw7, a Csn5-interacting F-box protein, as the E3 ligase that targeted topoIIα for degradation. Moreover, knockdown of CK2α, Csn5, or Fbw7 reversed HDAC inhibitor-induced topoIIα degradation. Mutational analysis indicates that the 1361SPKLSNKE1368 motif plays a crucial role in regulating topoIIα protein stability. This motif contains the consensus recognition sites for CK2 (SXXE), glycogen synthase kinase (GSK)3β (SXXXS), and Fbw7 (SPXXS). This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. This double phosphorylation facilitated the recruitment of Fbw7 to the phospho-degron 1361pSPKLpS1365 of topoIIα, leading to its ubiquitin-dependent degradation. Conclusion: This study shows a novel pathway by which HDAC inhibitors facilitate the selective degradation of topoIIα, which underlies the complexity of the functional role of HDAC in regulating tumorigenesis and aggressive phenotype in HCC cells. ? 2010 American Association for the Study of Liver Diseases.
SDGs
Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; 2 (2,4 dichlorophenyl) 3 (1 methyl 3 indolyl)maleimide; 2 [1 (3 dimethylaminopropyl) 3 indolyl] 3 (3 indolyl)maleimide; 4 (4 fluorophenyl) 2 (4 hydroxyphenyl) 5 (4 pyridyl)imidazole; ar 42; casein kinase II; COP9 signalosome; COP9 signalosome subunit 5; DNA topoisomerase (ATP hydrolysing); entinostat; F box protein; F box protein Fbw7; glycogen synthase kinase 3beta; histone deacetylase inhibitor; histone H3; serine; topoisomerase 2 alpha; topoisomerase 2 beta; ubiquitin; ubiquitin protein ligase E3; unclassified drug; vorinostat; animal cell; animal experiment; animal model; article; carcinoma cell; controlled study; correlation analysis; enzyme activation; enzyme degradation; enzyme mechanism; enzyme phosphorylation; female; histone acetylation; liver carcinogenesis; liver carcinoma; liver cell carcinoma; mouse; nonhuman; phenotype; priority journal; promoter region; protein degradation; protein expression; protein phosphorylation; protein stability; Animals; Antigens, Neoplasm; Carcinoma, Hepatocellular; Casein Kinase II; Cell Cycle Proteins; Cell Line, Tumor; DNA Topoisomerases, Type II; DNA-Binding Proteins; F-Box Proteins; Female; Gene Knockdown Techniques; Glycogen Synthase Kinase 3; Histone Deacetylase Inhibitors; Humans; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Mice; Mice, Nude; Peptide Hydrolases; Phenylbutyrates; Phosphorylation; Ubiquitin-Protein Ligases
Type
journal article