API

Relationship: 1997

Title

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Histone acetylation, increase leads to Cell cycle, disrupted

Upstream event

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Histone acetylation, increase

Downstream event

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Cell cycle, disrupted

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leading to testicular atrophy adjacent Moderate Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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Upon histone acetylation increase, cell cycle regulation is disrupted. Acetylation of the promoter region of the coding genes have a close correlation [Gurvich et al., 2004]. Transient histone hyperacetylation was sufficient for the activation of down-stream molecules involving cell cycle regulation [Wu et al., 2001]. Histone hyperacetylating agents butyrate and TSA induced mRNA expression of cell cycle regulator gene [Archer et al., 1998]. SAHA induced the accumulation of acetylated histones in the chromatin of the gene regulating cell cycle [Richon et al., 2000].

Evidence Supporting this KER

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Biological Plausibility

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Histone deacetylase inhibitors induce histone hyperacetylation and the activation of down-stream molecules leading to the cell cycle arrest, which suggests the close correlation between histone hyperacetylation and cell cycle arrest [Yuan et al., 2019]. The histone acetylation regulates the gene transcription through the promoter region of the coding gene, which may lead to the overexpression of cell cycle regulators [Richon et al., 2000; Struhl, 1998]. Histone deacetylase inhibition leads to acetylation of histone, inducing the expression of cyclin-dependent kinase inhibitors, followed by a cell-cycle arrest [Li and Seto, 2016].

Empirical Evidence

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  • MAA induced histone acetylation of H4 in prostate cancer cells including LNCaP, C4-2B, PC-3 and DU-145 parallel with cyclin dependent kinase inhibitor p21, a cell cycle regulator, mRNA level increase [Parajuli et al., 2014].
  • HDIs accumulated acetylation of histones and induced cell cycle regulator p21 protein and mRNA expression [Richon et al., 2000; Wu et al., 2001].

Uncertainties and Inconsistencies

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The histone acetylation causes cell cycle disruption in several pathways, in which the specific molecule involvement remains uncertain.

Quantitative Understanding of the Linkage

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Histone acetylation occurs in dose-dependent manner with the treatment of chidamide for 48 hrs [Yuan et al., 2019]. The expression of proteins related to G0/G1 cell cycle arrest, p21 and phosphorylated p53 is increased in dose-dependent manner [Yuan et al., 2019].

Response-response Relationship

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Dose-response of histone acetylation and expression of p21 and phosphorylated p53 showed that treatment with 0.5, 1, or 2 micro mol/l of chidamide for 48hrs induced histone acetylation in RPMI8226 myeloma cells, while 2, 4, or 8 micro mol/l of chidamide for 48 hrs induced histone acetylation in U266 myeloma cells [Yuan et al., 2019]. Chidamide treatment in 0.5, 1, or 2 micro mol/l in RPMI8226 or 2, 4, or 8 micro mol/l in U266 induced G0/G1 arrest in the myeloma cells [Yuan et al., 2019]. Dose-response of valproic acid (VPA) showed that 5, 10, and 20 mM of VPA inhibited HDAC6 and HDAC7 activity in 293T cells, and 0.1-2 mM of VPA induced acetylation of lysine in H3 in U937 cells [Gurvich et al., 2004]. The p21 protein level was induced with the treatment of 0.25-2 mM of VPA in U937 cells [Gurvich et al., 2004].

Time-scale

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Time course for histone H4 hyperacetylation in response to repeated doses of TSA every 8 hrs showed that histone hyperacetylation was peaked in 12 hrs in 8-fold increase and showed 5-fold increase in 24 hrs compared to control [Wu et al., 2001]. TSA (0.3 uM) induced cell cycle regulator p21 mRNA expression in 1 hr after stimulation and the induction is returned to the basal level in 24 hrs [Wu et al., 2001]. Sodium butyrate (5 mM) and repetitive doses of TSA (0.3 uM, every 8 hrs) induced the p21 mRNA level in 24 hrs in HT-29 cells [Wu et al., 2001]. Acetylation of p21 promoter and p21 mRNA induction were correlated in treatment of valproic acid and analogs [Gurvich et al., 2004]. MAA-induced acetylation increases in histones H3 and H4 was occurred in 4, 8, 12 hrs and returned to basal level in 24 hrs after the treatment in rat testis [Wade et al., 2008].

Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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The relationship between increased histone acetylation and p21 expression increase is likely well conserved between species.

  • Chidamide induced histone acetylation and cell cycle arrest in RPMI8226 and U266 human myeloma cells (Homo sapiens) [Yuan et al., 2019].
  • TSA and sodium butyrate induced cell cycle regulator p21 mRNA expression in HT-29 human colon carcinoma cells (Homo sapiens) [Wu et al., 2001].
  • VPA increased acetylation of histone H3 from 3 hrs to 72 hrs after the treatment, and increased p21 expression in 24 hrs after the treatment in K562 cells (Homo sapiens) [Gurvich et al., 2004].
  • Scriptaid, a HDI, up-regulated p21 mRNA expression in mouse embryonic kidney cells (Mus musculus) [Chen et al., 2011].

References

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Archer, S.Y. et al. (1998), "p21WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells", Proc Natl Acad Sci USA 95:6791-6796

Chen, S. et al. (2011), "Histone deacetylase (HDAC) activity for embryonic kidney gene expression, growth, and differentiation", J Biol Chem 286:32775-32789

Gurvich, N. et al. (2004), "Histone deacetylase is a target of valproic acid-mediated cellular differentiation", Cancer Res 64:1079-1086

Li, Y. and Seto, E. (2016), "HDACs and HDAC inhibitors in cancer development and therapy", Cold Spring Harb Perspect Med 6:a026831

Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313

Richon, V.M. et al. (2000), "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation", Proc Natl Acad Sci 97:10014-10019

Struhl, K. (1998), "Histone acetylation and transcriptional regulatory mechanisms", Gene Dev 12:599-606

Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831

Wu, J.T. et al. (2001), "Transient vs prolonged histone hyper acetylation: effects on colon cancer cell growth, differentiation, and apoptosis", Am J Physiol Gastrointest Liver Physiol 280:G482-G490

Yuan, X. et al. (2019), "Chidamide, a histone deacetylase inhibitor, induces growth arrest and apoptosis in multiple myeloma cells in a caspase-dependent manner", Oncol Let 18:411-419