Overexpression of Histone Deacetylase and Amyloid Precursor Protein in Hepatocellular Carcinoma

Epigenetic modifications are involved in the pathogenesis of cancer, and histone deacetylase inhibitors are considered potential therapeutic agents. Histone tails undergo acetylation at lysine residues, which is associated with transcriptional activation. However, previous studies indicated that as histone deacetylase inhibitors, both (−)-epigallocatechin-3-gallate and valproic acid presented the effects of downregulation of amyloid precursor protein expression, which resulted in the induction of apoptosis. The downregulation of amyloid precursor protein, instead of conventionally activating gene expression as histone deacetylase inhibitor, was attractive. However, there was no relevant report on the correlation of the expression of amyloid precursor protein and histone deacetylase 1 in cancer. In the present study, we detected the expression of amyloid precursor protein and histone deacetylase 1 in hepatocellular carcinoma and adjacent tissues, as well as the correlations among histone deacetylase 1, amyloid precursor protein, and tumor stage. The results showed that the expressions of amyloid precursor protein and histone deacetylase 1 were significantly higher in hepatocellular carcinoma tissues than that in adjacent tissues ( P < .05), however, there was no statistical difference between amyloid precursor protein and histone deacetylase 1 with tumor stages. The present findings provided more foundation for the study on amyloid precursor protein metabolism in cancer, especially on the regulation of amyloid precursor protein by histone deacetylases.

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Expression of different histone deacetylases and functional effects of histone deacetylase inhibitors in hepatocellular carcinoma

Zeitschrift für Gastroenterologie ◽

10.1055/s-0037-1612774 ◽

2018 ◽

Vol 56 (01) ◽

pp. E2-E89

Author(s):

P Dietrich ◽

K Freese ◽

W Thasler ◽

C Hellerbrand

Keyword(s):

Hepatocellular Carcinoma ◽

Histone Deacetylase ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors

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Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein

Blood ◽

10.1182/blood-2006-02-003418 ◽

2006 ◽

Vol 109 (4) ◽

pp. 1373-1380 ◽

Cited By ~ 26

Author(s):

Jana Vlasáková ◽

Zora Nováková ◽

Lenka Rossmeislová ◽

Michal Kahle ◽

Pavel Hozák ◽

...

Keyword(s):

Histone Deacetylase ◽

Transcriptional Activation ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

Trichostatin A ◽

Hdac Inhibitors ◽

Eukaryotic Cell ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

Interferon Α

Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.

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Neuroprotection by Histone Deacetylase-Related Protein

Molecular and Cellular Biology ◽

10.1128/mcb.26.9.3550-3564.2006 ◽

2006 ◽

Vol 26 (9) ◽

pp. 3550-3564 ◽

Cited By ~ 68

Author(s):

Brad E. Morrison ◽

Nazanin Majdzadeh ◽

Xiaoguang Zhang ◽

Aaron Lyles ◽

Rhonda Bassel-Duby ◽

...

Keyword(s):

Cell Death ◽

Histone Deacetylase ◽

Neuronal Death ◽

Histone Deacetylases ◽

Essential Feature ◽

Gene Promoter ◽

Related Protein ◽

Phosphatidylinositol 3 Kinase ◽

Histone Deacetylase 1 ◽

H3 Acetylation

ABSTRACT The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.

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Transcriptional activation of Alzheimer's β-amyloid precursor protein gene by stress

Molecular Brain Research ◽

10.1016/0169-328x(95)00131-b ◽

1995 ◽

Vol 33 (2) ◽

pp. 245-253 ◽

Cited By ~ 40

Author(s):

Nazneen N. Dewji ◽

Chau Do ◽

Richard M. Bayney

Keyword(s):

Amyloid Precursor Protein ◽

Transcriptional Activation ◽

Protein Gene ◽

Precursor Protein ◽

Amyloid Precursor Protein Gene ◽

Β Amyloid

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STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i3.22735 ◽

2018 ◽

Vol 10 (3) ◽

pp. 90

Author(s):

Avineesh Singh ◽

Harish Rajak

Keyword(s):

Molecular Docking ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Research Work ◽

3D Qsar ◽

Qsar Model ◽

Docking Studies ◽

Inhibition Activity ◽

Design Strategies ◽

Histone Deacetylase 1

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

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

Hepatology ◽

10.1002/hep.23964 ◽

2011 ◽

Vol 53 (1) ◽

pp. 148-159 ◽

Cited By ~ 27

Author(s):

Mei-Chuan Chen ◽

Chun-Han Chen ◽

Hsiao-Ching Chuang ◽

Samuel K. Kulp ◽

Che-Ming Teng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Carcinoma Cells ◽

Topoisomerase Iiα ◽

Hepatocellular Carcinoma Cells

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Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Molecules ◽

10.3390/molecules25030717 ◽

2020 ◽

Vol 25 (3) ◽

pp. 717 ◽

Cited By ~ 2

Author(s):

Na Zhao ◽

Feifei Yang ◽

Lina Han ◽

Yuhua Qu ◽

Di Ge ◽

...

Keyword(s):

Molecular Docking ◽

Histone Deacetylase ◽

Cell Lines ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

Human Cancer ◽

Immunoblot Analysis ◽

Docking Study ◽

Molecular Docking Study ◽

Human Cancer Cell Lines

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

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