Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells

Mei Chuan Chen, Chun-Han Chen, Hsiao Ching Chuang, Samuel K. Kulp, Che Ming Teng, Ching Shih Chen

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)148-159
Number of pages12
JournalHepatology
Volume53
Issue number1
DOIs
Publication statusPublished - Jan 2011
Externally publishedYes

Fingerprint

Type II DNA Topoisomerase
Histone Deacetylase Inhibitors
Hepatocellular Carcinoma
Phosphorylation
F-Box Proteins
Glycogen Synthase Kinase 3
Phenotype
Casein Kinase II
Histone Deacetylases
Ubiquitin-Protein Ligases
Protein Stability
Ubiquitin
Histones
Proteolysis
Carcinogenesis
Phosphotransferases
Pharmaceutical Preparations
Genes
Neoplasms

ASJC Scopus subject areas

  • Hepatology

Cite this

Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells. / Chen, Mei Chuan; Chen, Chun-Han; Chuang, Hsiao Ching; Kulp, Samuel K.; Teng, Che Ming; Chen, Ching Shih.

In: Hepatology, Vol. 53, No. 1, 01.2011, p. 148-159.

Research output: Contribution to journalArticle

Chen, Mei Chuan ; Chen, Chun-Han ; Chuang, Hsiao Ching ; Kulp, Samuel K. ; Teng, Che Ming ; Chen, Ching Shih. / Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells. In: Hepatology. 2011 ; Vol. 53, No. 1. pp. 148-159.
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