HDAC inhibition leads to induction of the p21 through chromosomal hyperacetylation on promoter regions of cell cycle regulatory genes [Falkenberg, 2014]. The HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), and MS-27-275 induced histone hyperacetylation and p21 up-regulation [Glaser, 2003].
In human pancreatic cancer cell lines, p21 up-regulation and histone H3 hyperacetylation by HDAC inhibitor AR-42 were observed [Henderson, 2016]. Furthermore, the oral administration of AR-42 at 50 mg/kg resulted in suppression of tumor in the pancreatic cancer cell xenograft and transgenic KPfl/flC (LSL-KrasG12D; Trp53flox/flox; Pdx-1-Cre) mouse model [Henderson, 2016].
HDAC inhibitor, methoxyacetic acid (MAA), up-regulated p21 mRNA level and acetylation of histone H3 and H4 [Parajuli, 2014].
The expression of p21 was up-regulated with 10 mM of MAA [Dayan, 2014].
HDIs-induced G1/S phase arrest occurs primarily through transcriptional changes in cell cycle regulatory genes, such as induction of the CDK inhibitors p21 (CDKN1A), p15INK4B (CDKN2B), p19INK4D (CDKN2D) and p57 (CDKN1C) [Falkenberg, 2014].
HDAC1-deficient embryonic stem cells showed decrease in cyclin-associated kinase activities and increase in p21WAF1/CIP1 [Lagger, 2002]. Expression of p21 is up-regulated in HDAC1-null embryos [Lagger, 2002].
HDIs induce expression of p21 via Sp1 binding sites in the p21 promoter [Gartel, 2002].
HDIs such as SAHA, TSA and MS-275 up-regulates p21 gene expression in T24 bladder carcinoma cells, which also suggests that HDAC inhibition leads to p21 up-regulation [Glaser, 2003].
Cyclin-dependent kinase (CDK) inhibitor p21 is up-regulated in HDAC1-deficient embryonic stem (ES) cells [Lagger, 2002].
In HDAC1-/- mouse embryonic fibroblasts, p21 level increase is observed, which indicates that HDAC suppression leads to p21 up-regulation [Zupkovitz, 2010].
Loss of HDAC1 in ES cells decreased proliferation and cyclin A- and cyclin E-associated kinase activity in the HDAC1 mutant cells [Lagger, 2002].
The HDAC inhibition-induced p21 up-regulation seems to contain several pathway cross-talks. The HDAC inhibition with sodium butyrate increases p53-dependent up-regulation of p21 [Saldanha, 2014]. The HDAC inhibition with 2-MAA induced p53 acetylation [Dayan, 2014]. HDAC inhibition with ST2783 induced acetylation of p53 [Zuco, 2011].
The exposure of 2-MAA (3, 10, 30 mM) on limbs for 3 hrs dose-dependently increased p21 mRNA level [Dayan, 2014]. The 2-MAA (3, 10, and 30 mM) dose-dependently induced acetylation on histone 3 lysine 9 (H3K9Ac) and histone 4 lysine 12 (H4K12Ac) at 1, 3, 6 and 24hr [Dayan, 2014]. The expression of p21 in A431 lung carcinoma cells and H1975 skin carcinoma cells stimulated with gefitinib loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (GNPs) was increased in more than 3-fold compared to the cells without treatment [Kaur, 2013]. GNPs hyperacetylate histone H3 via histone acetyltransferases p300/CBP [Kaur, 2013].
Time course for histone H4 hyperacetylation in response to in 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 JT].
The exposure of 2-MAA on mouse limbs in vitro induced histone hyperacetylation and p21 expression increase (Mus musculus) [Dayan, 2014]. HDAC-deficient embryonic stem cells demonstrated up-regulation of p21 in mice (Mus musculus) [Lagger, 2002]. HDAC inhibitor, AR-42 induced histone hyperacetylation and p21 up-regulation in human pancreatic cancer cells (Homo sapiens) [Henderson, 2016].