Histone deacetylase inhibitors increase p21^WAF1 and induce apoptosis of human myeloma cell lines independent of decreased IL‐6 receptor expression

Abstract

Histone deacetylase (HDAC) inhibitors cause growth arrest and apoptosis of cancer cells by both p21-dependent and independent mechanisms. Decreased expression of growth factor receptors may be a key factor in the p21-independent mechanism, although this has not been directly tested. We have tested the effects of sodium butyrate and trichostatin A on human myeloma cell lines and have observed G1 arrest and apoptosis associated with increased expression of p21(WAF1), Bax, Rb dephosphorylation, and decreased IL-6 receptor (IL-6R) expression. Experiments to determine the role of disruption of IL-6 signaling as a result of decreased IL-6 receptor expression in mediating these effects were conducted using a stable transfectant of the OPM-2 line which constitutively expressed the IL-6 receptor. Our results indicated that decreased IL-6R expression was not required for induction of p21(WAF1) or apoptosis. Thus, HDAC inhibitors appear to activate multiple cellular pathways, leading to growth arrest and apoptosis, and their use in the treatment of myeloma, particularly in combination with other agents, warrants further investigation.

Gene modulation associated with inhibition of liver regeneration in hepatitis B virus X transgenic mice

“…In the group of genes that was found to be down-regulated in the liver of HBxtransgenic mice, we observed several genes like SAA3, aldolase A, creatine kinase, phospholipase A2 that have been reported elsewhere as up-regulated during the course of liver regeneration [22][23][24] . Interestingly, down-regulation of histone deacetylase and up-regulation of DNA repair genes (Rad52 and MSH6) observed in our study in HBx-transgenic mice after PH have, in agreement with other reports, similar effect on the cell cycle by inducing cell cycle arrest [25][26][27][28] . Furthermore, it has previously been reported that HBx expression may interfere with nucleotide excision repair mechanisms [29,30] and interact with the DNA repair protein [31,32] .…”

“…In this context, we showed that HBx down-regulated HDAC10 and up-regulated DNA repair gene (Rad52 and MSH6) expression, which may have a similar impact on the cell cycle. Indeed, HDAC inhibition causes cell cycle arrest due to an increase in the expression of p21 WAF1/Cip1 and Rb [25,26,41,42] . Moreover, it has been reported that Rad52 over-expression affects cell cycle regulation by delaying the exit from G1 [27] , and that MSH6 protein induces apoptosis by activation of p53 [28] .…”

5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

“…This is in line with previous reports that DNA demethylation is not required for p21 induction but results from treatment with a histone deacetylase inhibitor. 33 In addition, reduction of DNMTase level by antisense oligonucleotides could increase p21 protein independently of the methylation status of p21/ CDKN1A in cancer cell lines. 34,35 The lack of p21 promoter methylation led us to postulate p73 as a target of 5-Aza-CdR-mediated demethylation in AML.…”

The emerging role of lysine acetylation of non-nuclear proteins

“…Indeed, HDAC inhibitors trigger cell cycle arrest, apoptosis, autophagy, differentiation and also inhibit metastasis and angiogenesis of cancerous cells through multiple mechanisms [60]. HDAC inhibitors alter the levels of cell cycle regulatory proteins such as p21 WAF1/CIP1 and p27 KIP1 and cause Rb hyperphosphorylation [61][62][63][64][65][66][67]. They actually trigger cell apoptosis by inducing proapoptotic members such as Bax, Bak, Nova, Bim and Puma and also by decreasing the expression of anti-apoptotic proteins such as Bcl-2, Bcl-X L and Mcl-1 [68][69][70][71][72].…”