Upstream eventHistone acetylation, increase
Cell cycle, disrupted
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||Moderate||Moderate|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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
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].
- 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
The histone acetylation causes cell cycle disruption in several pathways, in which the specific molecule involvement remains uncertain.
Quantitative Understanding of the Linkage
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].
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 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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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].
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