p21waf1/Cip1 partially mediates apoptosis in hepatocellular carcinoma cells

Svechnikova, Irina; Ammerpohl, Ole; Ekström, Tomas J.

doi:10.1016/j.bbrc.2006.12.222

Cited by 16 publications

(12 citation statements)

References 18 publications

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“…As shown in Fig. 3C, p21 waf1 expression was undetectable in untreated Hep3B cells but increased substantially after TSA treatment in a dose-dependent manner after 24 h, as shown previously (40). Furthermore, since TSA treatment results in global hypomethylation, we elucidated the role of DNA methylation for p21 waf1 expression.…”

Section: Vol 31 2011supporting

confidence: 83%

“…They suggested that this is an important linker region between the methyltransferase activity domain and the Nterminal regulatory domain of DNMT1. Therefore, HDACi treatment may induce hyperacetylation of DNMT1, resulting in a disturbance of DNMT1 binding to other nuclear (40). Also, it has been reported that p21 waf1 and DNMT1 share the same binding site on proliferating cell nuclear antigen PCNA (5).…”

Section: ϫ2mentioning

confidence: 99%

“…Waf1 -driven apoptosis (40), in relation to cell density (17), and on changes in DNA methylation. The great complexity of the problem-a low number of DNMT1 molecules in comparison to the surrounding molecules (concentrations of the order 10 to 500 nM), fast molecular interactions (typically characterized by on-off rates of the order 10 5 to 10 8 M Ϫ1 s Ϫ1 ), and rapid molecular movement (diffusion coefficients of the order 10 Ϫ12 to 10 Ϫ10 m 2 s Ϫ1 )-requires ultrasensitive methods with high spatial (submicrometer) and temporal (submillisecond resolution and single molecule sensitivity).…”

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confidence: 99%

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Genomic DNA Hypomethylation by Histone Deacetylase Inhibition Implicates DNMT1 Nuclear Dynamics

Arzenani

Zade

et al. 2011

Molecular and Cellular Biology

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Epigenetic modifications of chromatin play an important role in differentiation, aging, and tumorigenesis (41). Major epigenetic mechanisms include DNA methylation and covalent posttranslational modification of histone tails. These events switch chromatin between relatively "open" (expressed) and "closed" (suppressed) structures. Although there are several different histone modifications, the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs) are considered important regulators of chromatin structure (28). DNA methylation is an important epigenetic modification in the vertebrate genome which occurs mainly on cytosines located in CpG dinucleotide sequences (2). DNA methylation patterns are established by DNA methyltransferase 3a (DNMT3a) and DNMT3b, which are de novo DNA methyltransferases (DNMTs), and are mainly propagated by DNMT1, a maintenance methyltransferase (39). DNA methyltransferases are involved in the aberrant DNA methylation patterns frequently found in cancer cells (21). In addition, there is growing evidence that inappropriate gene expression by epigenetic events is crucial for the initiation and progression of cancer. These epigenetic abnormalities, including epigenetic silencing of tumor suppressor genes by abnormal promoter methylation, are likely to play an important role in tumor growth and metastasis when a substantial number of genes can be inactivated by DNA methylation in a tumor (20). In addition to DNA methylation, genome-wide changes in histone modifications are also found in cancer cells. Loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4 have been reported as common hallmarks of human cancer (11).New insights into the high prevalence of epigenetic changes in cancer have led to novel therapeutic approaches in oncology that rely on the dynamic nature of epigenetic factors. The main idea behind these approaches is that abnormal epigenetic marks leading to gene silencing may be reversed. Two categories of drugs, affecting histone acetylation and DNA methylation, are currently considered in epigenetic therapy of cancer. In myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are already in clinical use (15,23). HDACi can open up chromatin by causing hyperacetylation of histones H3 and H4 (49). DNMTi, such as 5-aza-deoxycytidine, can induce genomic DNA hypomethylation (35). However, some gene promoters are not readily activated with either of the two inhibitors alone, but there are reports showing that HDACi and DNMTi can act synergistically to reactivate silenced genes (12,47). Therefore, the functional interaction between HDACs and DNMTs has been a key issue in epigenetic research. Trichostatin A (TSA), a general inhibitor for class I and II HDACs, has also been shown to reactivate methylation-silenced genes even in the absence of DNMT inhibitors (25). In addition, it has been reported that TSA decreases DNMT3b mRNA levels in endo...

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Section: Vol 31 2011supporting

confidence: 83%

Section: ϫ2mentioning

confidence: 99%

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confidence: 99%

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Genomic DNA Hypomethylation by Histone Deacetylase Inhibition Implicates DNMT1 Nuclear Dynamics

Arzenani

Zade

et al. 2011

Molecular and Cellular Biology

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“…Interestingly, p21 expression tended to be reduced in GFAP-IL6 in our experiment. p21 is involved in cell cycle and a very well known tumor suppressor gene involved in apoptosis in many cancer cell types as several antitumoral treatments actions are mediated by this factor (Svechnikova et al, 2007). Furthermore, growth arrest and DNA-damage-inducible 45 beta (gadd45b) also showed a trend to be decreased in GFAP-IL6 mice.…”

Section: Il-6 Production Decreases the Expression Of Proapoptotic Genmentioning

confidence: 97%

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Quintana

Molinero

Borup

et al. 2007

Developmental Neurobiology

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Interleukin-6 (IL-6) is one of the key players in the response of the brain cortex to injury. We have described previously that astrocyte-driven production of IL-6 (GFAP-IL6) in transgenic mice, although causing spontaneous neuroinflammation and long term damage, is beneficial after an acute (freeze) injury in the cortex, increasing healing and decreasing oxidative stress and apoptosis. To determine the transcriptional basis for these responses here we analyzed the global gene expression profile of the cortex, at 0 (unlesioned), 1 or 4 days post lesion (dpl), in both GFAP-IL6 mice and their control littermates. GFAP-IL6 mice showed an increase in genes associated with the inflammatory response both at 1 dpl (Iftm1, Endod1) and 4 dpl (Gfap, C4b), decreased expression of proapoptotic genes (i.e. Gadd45b, Clic4, p21) as well as reduced expression of genes involved in the control of oxidative stress (Atf4). Furthermore, the presence of IL-6 altered the expression of genes involved in hemostasis (Vwf), cell migration and proliferation (Cap2), and synaptic activity (Vamp2). All these changes in gene expression could underlie the phenotype of the GFAP-IL6 mice after injury, but many other possible factors were also identified in this study, highlighting the utility of this approach for deciphering new pathways orchestrated by IL-6.

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“…The obtained results suggest an important role for p21 in mediating the apoptotic effect of HDACIs. [82] An experimental study has investigated the antineoplastic effect of TSA and phenylbutyrate on the human glioblastoma cell lines GBM-29, U-343 MG, and U-343 MGa Cl. 2 : 6, giving the following results: (i) TSA and phenylbutyrate have induced apoptosis in the three cell lines in a dose-and time-dependent manner, and caspase-3 activation has been detected in all three cell lines; (ii) U-343 MG cells have been more sensitive to the apoptotic effect of HDACI compared with U-343 MGa Cl.…”

Section: Phenylbutyrate and Cancermentioning

confidence: 99%