Activation of NF-κB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: its implication for resistance to apoptosis

Yk, Kim; Lee, EK; Kang, Jaeku; Ja, Kim; Js, You; Jh, Park; Seo, Dong Wan; Hwang, JW; Sn, Kim; Hy, Lee; Hw, Lee; Jw, Han

doi:10.1038/sj.cdd.4401915

Cited by 40 publications

(37 citation statements)

References 40 publications

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“…HDACIs-Previous studies have shown that HDACIs activate NF-B in diverse cell types (11,12,34). To characterize this phenomenon in greater detail, a time course analysis of NF-B activation was conducted (Fig.…”

Section: Induction Of Nf-b Activity and Regulation Of Ros Bymentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, ␥-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-B pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-B activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.Chromatin structure and gene expression are regulated by reversible acetylation of lysine residues in histone tails, a process comprising a component of the histone code (1). Histone acetylation is regulated reciprocally by histone deacetylases (HDACs) 2 and histone acetylase transferases (2). Histone deacetylase inhibitors, a group of structurally diverse compounds, have shown encouraging activity in certain hematopoietic malignancies, including cutaneous T-cell lymphoma and acute leukemia (3,4). Numerous mechanisms have been proposed to account for HDACI-mediated lethality, including oxidative damage, up-regulation of death receptors or proapoptotic proteins (e.g. Bim), down-regulation of anti-apoptotic proteins, and more recently, DNA damage induction and/or interference with DNA repair proteins (3,5,6).HDACIs also increase acetylation of various non-histone proteins including chaperone proteins (7), DNA repair proteins (e.g. Ku70) (8), and transcription factors, e.g. YY-1, E2F, and NF-B (9, 10). Of the latter, NF-B is a particularly important determinant of HDACI actions, particularly proliferation, differentiation, and cell death (11-13). NF-B consists of a family of proteins including p65/RelA, RelB, c-Rel, p105, p100, p52, and p50, which form homo-and heterodimers, of which p65/ p50 is the most abundant (14). Various cytokines (e.g. TNF␣, interleukin-1, and lipopolysaccharides) and environmental stresses trigger the classical NF-B pathway by activating the IKK complex, which consists of IKK␣, IKK␤, and IKK␥/NEMO (NF-B-essential modulator) (15). This leads to phosphorylation (Ser-32/Ser-36), ubiquitination, and proteasomal degradation of IB␣, resulting in p65 nuclear translocation, DNA binding, and activation of prosurvival genes, including . Other stimuli (e.g. CD-40 ligation, lymphotoxin-␤, and B-cell-activating factor (BAFF)) activate the alternative (noncanonical) NF-B pathway through a complex consisting of NF-B-inducing kinase (NIK) and IKK␣ but not IKK␤ (16). A third, atypical, UV light-associated pathway activates p65 via p38 mitogen-activated protein kinase (MAPK) and CSII * This work was supported, in whole or in part, by National Institutes of Health Grants CA63753, CA93738, and CA100866 from the National Cancer Institute, the Leukemia and Lymphoma Society of America, and Lymphoma SPORE Award 1P50 CA130805. This work was al...

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Section: Induction Of Nf-b Activity and Regulation Of Ros Bymentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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“…The discrepancy may be due to the activation of NF-κB by BST204 in HT-29 cells, which is essential for cell survival, because BST204 was able to activate the transcription of NF-κB reporter gene (unpublished data). Consistent with our observation, NF-κB activation has been demonstrated to contribute to resistance of cancer cells to apoptotic potential of HDAC inhibitor apicidin which has been shown to be a potent anti-proliferative agent Kim et al, 2006a;2006b;Eun et al, 2007).…”

Section: Discussionsupporting

confidence: 77%

A Fermented Ginseng Extract, BST204, Inhibits Proliferation and Motility of Human Colon Cancer Cells

Park¹,

Lee²,

Ann³

et al. 2011

Biomolecules and Therapeutics

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“…DNMT1 knockdown induces the activation of capase-3, resulting in subsequent cleavage of PARP (Figure 7c). However, treatment of HeLa cells with apicidin does not cause cleavages of neither caspase-3 nor PARP (Figure 7c), consistent with our previous observation showing that apicidin does not induce apoptosis of HeLa cells (Kim et al, 2006). The results suggest that DNMT1 might be a good target for inducing apoptosis of HeLa cells.…”

Section: Knock Down Of Dnmt1 Induces Expression Of P21supporting

confidence: 81%

Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells

Kang

Lee

et al. 2007

Oncogene

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Dysregulation of DNA methyltransferase (DNMT)1 expression is associated with cellular transformation, and inhibition of DNMT1 exerts antitumorigenic effects. Here, we report that DNMT1 abnormally expressed in HeLa cells is downregulated by a histone deacetylase (HDAC) inhibitor apicidin, which is correlated with induction of repressive histone modifications on the promoter site. Apicidin selectively represses the expression of DNMT1 among DNMTs in HeLa cells, independent of cell cycle arrest at G 0 /G 1 . Furthermore, apicidin causes a significant reduction in the recruitment of RNA polymerase II into the promoter. Chromatin immunoprecipitation analysis shows that even though apicidin causes global hyperacetylation of histone H3 and H4, localized deacetylation of histone H3 and H4 occurs at the E2F binding site, which is accompanied by the recruitment of pRB and the replacement of P/CAF with HDAC1 into the sites. In addition, K4-trimethylated H3 on nucleosomes associated with the transcriptional start site is depleted following apicidin treatment, whereas repressive markers, K9-and K27-trimethylation of H3 are enriched on the site. The downregulation of DNMT1 expression seems to require de novo protein synthesis, because the apicidin effect is antagonized by cycloheximide treatment. Moreover, knock down of DNMT1 with siRNA induces the apoptosis of HeLa cells, indicating that downregulation of DNMT1 might be a good strategy for therapeutics of human cervix cancer. Collectively, our findings will provide a mechanistic rationale for the use of HDAC inhibitors in cancer therapeutics.

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Activation of NF-κB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: its implication for resistance to apoptosis

Cited by 40 publications

References 40 publications

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

A Fermented Ginseng Extract, BST204, Inhibits Proliferation and Motility of Human Colon Cancer Cells

Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells

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