A high degree of developmental plasticity enables plants to adapt to continuous, often unfavorable and unpredictable changes in their environment. At the molecular level, adaptive advantages for plants are primarily provided by epigenetic machinery including DNA methylation, histone modifications, and the activity of noncoding RNA molecules. Using a mass spectrometry-based proteomic approach, we examined the levels of acetylated histone peptide forms in Arabidopsis plants with a loss of function of histone deacetylase 6 (HDA6), and in plants germinated in the presence of HDA inhibitors trichostatin A (TSA) and sodium butyrate (NaB). Our analyses revealed particular lysine sites at histone sequences targeted by the HDA6 enzyme, and by TSA- and NaB-sensitive HDAs. Compared with plants exposed to drugs, more dramatic changes in the overall profiles of histone post-translational modifications were identified in hda6 mutants. However, loss of HDA6 was not sufficient by itself to induce hyperacetylation to the maximum degree, implying complementary activities of other HDAs. In contrast to hda6 mutants that did not exhibit any obvious phenotypic defects, the phenotypes of seedlings exposed to HDA inhibitors were markedly affected, showing that the effect of these drugs on early plant development is not limited to the modulation of histone acetylation levels.
- Klíčová slova
- Arabidopsis thaliana, epigenetics, histone, mass spectrometry, post-translational modifications, sodium butyrate, trichostatin A,
- MeSH
- Arabidopsis genetika růst a vývoj MeSH
- histondeacetylasy genetika MeSH
- histonový kód účinky léků genetika MeSH
- inhibitory histondeacetylas farmakologie MeSH
- klíčení genetika MeSH
- kyselina máselná farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- metylace DNA účinky léků MeSH
- proteiny huseníčku antagonisté a inhibitory genetika MeSH
- proteomika * MeSH
- regulace genové exprese u rostlin MeSH
- semenáček účinky léků genetika MeSH
- umlčování genů MeSH
- vývoj rostlin účinky léků genetika MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AT5G63110 protein, Arabidopsis MeSH Prohlížeč
- histondeacetylasy MeSH
- inhibitory histondeacetylas MeSH
- kyselina máselná MeSH
- kyseliny hydroxamové MeSH
- proteiny huseníčku MeSH
- trichostatin A MeSH Prohlížeč
Histone modifications play a key role in the epigenetic regulation of gene transcription in cancer cells. Histone acetylations are regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are increased in ovarian carcinomas and they are involved in carcinogenesis and resistance to chemotherapeutic agents. In our study we investigated anticancer effect of HDAC inhibitor sodium butyrate (NaBu) on cisplatin-sensitive and cisplatin-resistant ovarian cell lines A2780 and A2780cis. A2780 and A2780cis were treated with NaBu alone or in combination with cisplatin (CP). NaBu inhibited the growth of both cell lines and enhanced cytotoxic effect of CP. Exposure to NaBu for 24 h induced cell cycle arrest. The expressions of EMT-related genes and proteins were further investigated by qPCR and western blot analysis. Loss of E-cadherin has been shown to be crucial in ovarian cancer development. We found that NaBu dramatically induce expression of E-cadherin gene (CDH1) and protein levels in A2780 and A2780cis. We investigated correlation between transcription and methylation of CDH1gene. Methylation level analysis in 32 CpG sites in CDH1 gene (promoter/exon1 regions) was performed using bisulfite NGS (Next Generation Sequencing). We found that cisplatin-resistant cell line A2780cis cells differ from their cisplatin-sensitive counterparts in the CDH1 methylation. Methylation in A2780cis cells is elevated compared to A2780. However, NaBu-induced expression of CDH1 was not accompanied by CDH1 demethylation. NaBu treatment induced changes in expression of EMT-related genes and proteins. Interestingly E-cadherin zinc finger transcriptional repressor SNAIL1 was upregulated in both cell lines. Mesenchymal marker vimentin was downregulated. Matrix metalloproteases (MMPs) are necessary for pericellular proteolysis and facilitate migration and invasion of tumour cells. NaBu induced mRNA expression of MMPs, mild changes in activities of gelatinases MMP2 and MMP9 were detected. Our data demonstrate that NaBu sensitizes cisplatin-resistant ovarian cancer cells, re-established E-cadherin expression, but it was not able to reverse the EMT phenotype completely.
- MeSH
- antitumorózní látky farmakologie MeSH
- buněčný cyklus účinky léků MeSH
- CD antigeny genetika MeSH
- chemorezistence genetika MeSH
- cisplatina farmakologie MeSH
- epigeneze genetická účinky léků MeSH
- epitelo-mezenchymální tranzice účinky léků genetika MeSH
- genetické markery MeSH
- histonový kód účinky léků MeSH
- inhibitory histondeacetylas farmakologie MeSH
- kadheriny genetika MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků farmakoterapie genetika patologie MeSH
- proliferace buněk účinky léků MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- CD antigeny MeSH
- CDH1 protein, human MeSH Prohlížeč
- cisplatina MeSH
- genetické markery MeSH
- inhibitory histondeacetylas MeSH
- kadheriny MeSH
- kyselina máselná MeSH
BACKGROUND: Haemanthamine (HA) and sodium butyrate (NaB) are promising candidates for chemotherapy as a treatment for cancer. PURPOSE: We aimed to determine the anticancer potential of HA and NaB, alone and in combination, in A2780 ovarian cancer cells and concurrently investigated anticancer potential in contrast to non-cancer human MRC-5 fibroblasts. METHODS: Antiproliferative effects were determined by WST-1 assay and by Trypan blue exclusion staining. Cell cycle distributions were studied by flow cytometry and protein levels were determined by Western blotting. RESULTS: The combination of HA and NaB caused a significant decrease in the proliferation of A2780 cells compared to the stand-alone treatment of cells by HA or NaB. This effect was less pronounced in non-cancer MRC-5 fibroblasts. In the later intervals, the number of A2780 living cells was strongly decreased by treatment using a combination of NaB and HA. This simultaneous application had no considerable effect in MRC-5 fibroblasts. The combination of NaB and HA led to the suppression of cells in the G1 phase and caused an accumulation of cells in the S and G2 phase in comparison to those treated with NaB and HA alone. Treatment of cells with NaB alone led to the activation of proteins regulating the cell cycle. Notably, p21WAF1/Cip1 was upregulated in both A2780 and MRC-5 cells, while checkpoint kinases 1 and 2 were activated via phosphorylation only in A2780 cells. Unexpectedly, NaB in combination with HA suppressed the phosphorylation of Chk2 on threonine 68 and Chk1 on serine 345 in A2780 cells and downregulated p21WAF1/Cip1 in both tested cell lines. The sensitization of cells to HA and NaB treatment seems to be accompanied by increased histone acetylation. NaB-induced acetylation of histone H3 and H4 and histone acetylation increased markedly when a combination of NaB and HA was applied. Whereas the most prominent hyperacetylation after HA and NaB treatment was observed in A2780 cells, the acetylation of histones occurred in both cell lines. CONCLUSION: In summary, we have demonstrated the enhanced activity of HA and NaB against A2780 cancer cells, while eliciting no such effect in non-cancer MRC-5 cells.
- Klíčová slova
- Cell death, Haemanthamine, Histone acetylation, Ovarian carcinoma cells, Sodium butyrate,
- MeSH
- acetylace MeSH
- aktivace transkripce účinky léků MeSH
- alkaloidy amarylkovitých farmakologie MeSH
- buněčné dělení účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- checkpoint kinasa 1 metabolismus MeSH
- checkpoint kinasa 2 metabolismus MeSH
- fenantridiny farmakologie MeSH
- fosforylace MeSH
- histony metabolismus MeSH
- inhibitor p21 cyklin-dependentní kinasy metabolismus MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy amarylkovitých MeSH
- CDKN1A protein, human MeSH Prohlížeč
- checkpoint kinasa 1 MeSH
- checkpoint kinasa 2 MeSH
- CHEK1 protein, human MeSH Prohlížeč
- CHEK2 protein, human MeSH Prohlížeč
- fenantridiny MeSH
- hemanthamine MeSH Prohlížeč
- histony MeSH
- inhibitor p21 cyklin-dependentní kinasy MeSH
- kyselina máselná MeSH
PURPOSE: Although beneficial effects of the dietary n-3 docosahexaenoic acid (DHA) or butyrate in colon carcinogenesis have been implicated, the mechanisms of their action are not fully clear. Here, we investigated modulations of composition of individual phospholipid (PL) classes, with a particular emphasis on cardiolipins (CLs), in colon cells treated with DHA, sodium butyrate (NaBt), or their combination (DHA/NaBt), and we evaluated possible associations between lipid changes and cell fate after fatty acid treatment. METHODS: In two distinct human colon cell models, foetal colon (FHC) and adenocarcinoma (HCT-116) cells, we compared patterns and composition of individual PL classes following the fatty acid treatment by HPLC-MS/MS. In parallel, we measured the parameters reflecting cell proliferation, differentiation and death. RESULTS: In FHC cells, NaBt induced primarily differentiation, while co-treatment with DHA shifted their response towards cell death. In contrast, NaBt induced apoptosis in HCT-116 cells, which was not further affected by DHA. DHA was incorporated in all main PL types, increasing their unsaturation, while NaBt did not additionally modulate these effects in either cell model. Nevertheless, we identified an unusually wide range of CL species to be highly increased by NaBt and particularly by DHA/NaBt, and these effects were more pronounced in HCT-116 cells. DHA and DHA/NaBt enhanced levels of high molecular weight and more unsaturated CL species, containing DHA, which was specific for either differentiation or apoptotic responses. CONCLUSIONS: We identified a wide range of CL species in the colon cells which composition was significantly modified after DHA and NaBt treatment. These specific CL modulations might contribute to distinct cellular differentiation or apoptotic responses.
- Klíčová slova
- Apoptosis, Butyrate, Cardiolipins, Colon cancer, Docosahexaenoic acid, Phospholipids,
- MeSH
- apoptóza účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- fosfolipidy chemie MeSH
- HCT116 buňky MeSH
- kaspasa 3 genetika metabolismus MeSH
- kolon cytologie účinky léků MeSH
- kyselina máselná farmakologie MeSH
- kyseliny dokosahexaenové farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CASP3 protein, human MeSH Prohlížeč
- fosfolipidy MeSH
- kaspasa 3 MeSH
- kyselina máselná MeSH
- kyseliny dokosahexaenové MeSH
Butyrate, a short-chain fatty acid produced by fermentation of dietary fiber, is an important regulator of colonic epithelium homeostasis. In this study, we investigated the impact of this histone deacetylase (HDAC) inhibitor on expression/activity of cytochrome P450 family 1 (CYP1) and on metabolism of carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in colon epithelial cells. Sodium butyrate (NaBt) strongly potentiated the BaP-induced expression of CYP1A1 in human colon carcinoma HCT116 cells. It also co-stimulated the 7-ethoxyresorufin-O-deethylase (EROD) activity induced by the 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical ligand of the aryl hydrocarbon receptor. Up-regulation of CYP1A1 expression/activity corresponded with an enhanced metabolism of BaP and formation of covalent DNA adducts. NaBt significantly potentiated CYP1A1 induction and/or metabolic activation of BaP also in other human colon cell models, colon adenoma AA/C1 cells, colon carcinoma HT-29 cells, or in NCM460D cell line derived from normal colon mucosa. Our results suggest that the effects of NaBt were due to its impact on histone acetylation, because additional HDAC inhibitors (trichostatin A and suberanilohydroxamic acid) likewise increased both the induction of EROD activity and formation of covalent DNA adducts. NaBt-induced acetylation of histone H3 (at Lys14) and histone H4 (at Lys16), two histone modifications modulated during activation of CYP1A1 transcription, and it reduced binding of HDAC1 to the enhancer region of CYP1A1 gene. This in vitro study suggests that butyrate, through modulation of histone acetylation, may potentiate induction of CYP1A1 expression, which might in turn alter the metabolism of BaP within colon epithelial cells.
- Klíčová slova
- Butyrate, CYP1A1, Colon epithelial cells, DNA adducts, Histone deacetylases, Polycyclic aromatic hydrocarbons,
- MeSH
- adukty DNA účinky léků metabolismus MeSH
- benzopyren metabolismus farmakokinetika MeSH
- beta-katenin metabolismus MeSH
- buňky HT-29 MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- HCT116 buňky MeSH
- histondeacetylasa 1 antagonisté a inhibitory metabolismus MeSH
- histony metabolismus MeSH
- inhibitory histondeacetylas farmakologie MeSH
- kolon účinky léků metabolismus MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- metabolická inaktivace MeSH
- zesilovače transkripce účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adukty DNA MeSH
- benzopyren MeSH
- beta-katenin MeSH
- CTNNB1 protein, human MeSH Prohlížeč
- CYP1A1 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- HDAC1 protein, human MeSH Prohlížeč
- histondeacetylasa 1 MeSH
- histony MeSH
- inhibitory histondeacetylas MeSH
- kyselina máselná MeSH
The short-chain and n-3 polyunsaturated fatty acids exhibit anticancer properties, and they may mutually interact within the colon. However, the molecular mechanisms of their action in colon cancer cells are still not fully understood. Our study focused on the mechanisms responsible for the diverse effects of sodium butyrate (NaBt), in particular when interacting with docosahexaenoic acid (DHA), in distinct colon cancer cell types, in which NaBt either induces cell differentiation or activates programmed cell death involving mitochondrial pathway. NaBt activated autophagy both in HT-29 cells, which are sensitive to induction of differentiation, and in nondifferentiating HCT-116 cells. However, autophagy supported cell survival only in HT-29 cells. Combination of NaBt with DHA-promoted cell death, especially in HCT-116 cells and after longer time intervals. The inhibition of autophagy both attenuated differentiation and enhanced apoptosis in HT-29 cells treated with NaBt and DHA, but it had no effect in HCT-116 cells. NaBt, especially in combination with DHA, activated PPARγ in both cell types. PPARγ silencing decreased differentiation and increased apoptosis only in HT-29 cells, therefore we verified the role of caspases in apoptosis, differentiation and also PPARγ activity using a pan-caspase inhibitor. In summary, our data suggest that diverse responses of colon cancer cells to fatty acids may rely on their sensitivity to differentiation, which may in turn depend on distinct engagement of autophagy, caspases and PPARγ. These results contribute to understanding of mechanisms underlying differential effects of NaBt, when interacting with other dietary fatty acids, in colon cancer cells.
- Klíčová slova
- Autophagy, Butyrate, Colon cancer, Differentiation, Docosahexaenoic acid, PPARγ,
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- autofagie účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- buňky HT-29 MeSH
- butyráty farmakologie MeSH
- HCT116 buňky MeSH
- kaspasa 3 genetika metabolismus MeSH
- kyselina máselná farmakologie MeSH
- kyseliny dokosahexaenové farmakologie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- nádory tračníku patologie MeSH
- PPAR gama genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- butyráty MeSH
- CASP3 protein, human MeSH Prohlížeč
- kaspasa 3 MeSH
- kyselina máselná MeSH
- kyseliny dokosahexaenové MeSH
- PPAR gama MeSH
Sodium butyrate, as a naturally occurring inhibitor of histone deacetylases (HDACI), is a non-toxic agent, with an ability to change histone acetylation and expression of large number genes. This study shows different effects of sodium butyrate on expression and transcription activity of the androgen receptor in cancer (LNCaP, C4-2) and normal (RWPE-1) prostate cells. Moreover, we studied the coregulator expressions and histone acetylation alteration in cancer and normal cells. Coregulators, coactivators as well as corepressors, play an important role in AR-mediated growth and progression of prostate cancer. There is a competition between coactivators and corepressors for binding on the AR and therefore the changes in coregulators expression and ratio could be important for prostate cancer survival. Our study was focused on two coregulators, SMRT and p300, which interact with AR in multiprotein complex and affect the AR transcription activity. Our data indicate that sodium butyrate has an effect on AR coregulators expression, transcription activity and histone acetylation in cancer cells, but there is only minimal effect in normal cells. In addition, the results of changes in acetylation level on lysine residues of histone H4 after sodium butyrate treatment confirm its epigenetic effect on prostate cancer cells.
- MeSH
- acetylace MeSH
- androgenní receptory genetika metabolismus MeSH
- buněčné linie MeSH
- histony metabolismus MeSH
- inhibitory histondeacetylas farmakologie MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty metabolismus MeSH
- prostata cytologie MeSH
- prostatický specifický antigen metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- androgenní receptory MeSH
- histony MeSH
- inhibitory histondeacetylas MeSH
- kyselina máselná MeSH
- prostatický specifický antigen MeSH
Androgen receptor (AR) expression in prostate cancer (CaP) cells varies due to the multiple changes including epigenetic modifications such as DNA methylation and histone deacetylation. DNA methyltransferase and histone deacetylase inhibitors are promising for the treatment of CaP. The aim of our study was to analyze the 5-aza-2'-deoxycytidine (Aza‑dC) and sodium butyrate (NaB) effects on CaP cells with modified AR gene expression. The androgen-independent human prostate cancer cell lines PC3 (lacking a functional AR) and DU145 (strongly limited expression due to methylations in the AR gene) were used. PCR of bisulfite-modified DNA and RT-PCR with bisulfite-sequencing were used for AR gene analysis of DU145 and PC3 cells following their treatment with Aza-dC and/or NaB. Re-acetylated histones around the AR gene were detected by conventional PCR of immunoprecipitated DNA obtained from treated cells. In both cell lines without the AR expression, the combined treatment was followed with significant decrease of cell viability. The co-treatment of DU145 cells caused site-specific demethylation in the AR promoter region followed by gene re-expression and increased acetylation in histones H3 and H4. The co-treatment with Aza-dC and NaB was the most effective in demethylation and re-expression of the AR gene. In the AR gene promoter, the location and density of deme-thylated CpGs indicated the existence of distinct promoter hot spot that could be a target of AR gene inactivation therapy of CaP patients during androgen deprivation.
- MeSH
- 5' nepřekládaná oblast MeSH
- acetylace účinky léků MeSH
- androgenní receptory biosyntéza genetika metabolismus MeSH
- androgeny genetika metabolismus MeSH
- azacytidin analogy a deriváty farmakologie MeSH
- decitabin MeSH
- DNA genetika MeSH
- histondeacetylasy genetika metabolismus MeSH
- histony genetika metabolismus MeSH
- inhibitory histondeacetylas farmakologie MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- methyltransferasy antagonisté a inhibitory genetika metabolismus MeSH
- metylace DNA účinky léků MeSH
- nádorové buněčné linie MeSH
- nádory prostaty rezistentní na kastraci farmakoterapie enzymologie genetika metabolismus MeSH
- promotorové oblasti (genetika) účinky léků genetika MeSH
- viabilita buněk účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 5' nepřekládaná oblast MeSH
- androgenní receptory MeSH
- androgeny MeSH
- AR protein, human MeSH Prohlížeč
- azacytidin MeSH
- decitabin MeSH
- DNA MeSH
- histondeacetylasy MeSH
- histony MeSH
- inhibitory histondeacetylas MeSH
- kyselina máselná MeSH
- methyltransferasy MeSH
We have examined the effect of sodium butyrate (SB) on the viability of normal peripheral blood lymphocytes (PBLs) in vitro and the effect of this agent on the expression of 20 apoptosis-related genes. Data suggest that PBL treated with 2 mmol L(-1) SB resisted for at least 8 h the destructive activity of the agent, but eventually 30% of cells died within 72 h. As documented by flow cytometry and cytochrome c release study, cells underwent mitochondrial-derived apoptosis. While the expression of the majority of genes examined by RT-PCR and Western blots remained indifferent to 2 mmol L(-1) SB, the cellular levels of BimEL, c-myc, p53, and p21(WAF1) varied profoundly with the time of SB treatment. The Bax activator BimEL increased rapidly, driving cells toward apoptosis likely controlled by c-myc and p21(WAF1) activities. The c-myc, exercising the role of mediator of the function of BimEL and inhibitor of p21(WAF1) expression, decreased significantly for several hours after adding SB but within 48 h it returned to close to its original value. An apoptosis inhibitor and executive caspase substrate p21(WAF1) increased early at the beginning of treatment but subsequently, within a time frame of 72 h, profoundly dropped in terms of both a caspase-dependent and caspase-independent way. We suggest that variations in c-myc and p21(WAF1) expression delay apoptosis making PBL resistant to SB for several hours, and together with fast catabolism of SB in vivo protect PBL against the destructive activity of this anti-cancerous metabolite of colonic bacteria.
- MeSH
- aktivace enzymů MeSH
- apoptóza účinky léků MeSH
- cytochromy c metabolismus MeSH
- inhibitor p21 cyklin-dependentní kinasy genetika metabolismus MeSH
- intracelulární membrány účinky léků MeSH
- kaspasy metabolismus MeSH
- kolagen typ XI metabolismus MeSH
- kultivované buňky MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- lymfocyty účinky léků metabolismus MeSH
- membránové proteiny genetika metabolismus MeSH
- mitochondrie účinky léků MeSH
- protein BCL2L11 MeSH
- proteiny regulující apoptózu genetika metabolismus MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- protoonkogenní proteiny genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- BCL2L11 protein, human MeSH Prohlížeč
- Bcl2l11 protein, mouse MeSH Prohlížeč
- CDKN1A protein, human MeSH Prohlížeč
- COL11A2 protein, human MeSH Prohlížeč
- cytochromy c MeSH
- inhibitor p21 cyklin-dependentní kinasy MeSH
- kaspasy MeSH
- kolagen typ XI MeSH
- kyselina máselná MeSH
- membránové proteiny MeSH
- MYC protein, human MeSH Prohlížeč
- Perp protein, mouse MeSH Prohlížeč
- protein BCL2L11 MeSH
- proteiny regulující apoptózu MeSH
- protoonkogenní proteiny c-myc MeSH
- protoonkogenní proteiny MeSH
- reaktivní formy kyslíku MeSH
The effects of the histone deacetylase inhibitors (HDACi) trichostatin A (TSA) and sodium butyrate (NaBt) were studied in A549, HT29 and FHC human cell lines. Global histone hyperacetylation, leading to decondensation of interphase chromatin, was characterized by an increase in H3(K9) and H3(K4) dimethylation and H3(K9) acetylation. The levels of all isoforms of heterochromatin protein, HP1, were reduced after HDAC inhibition. The observed changes in the protein levels were accompanied by changes in their interphase patterns. In control cells, H3(K9) acetylation and H3(K4) dimethylation were substantially reduced to a thin layer at the nuclear periphery, whereas TSA and NaBt caused the peripheral regions to become intensely acetylated at H3(K9) and dimethylated at H3(K4). The dispersed pattern of H3(K9) dimethylation was stable even at the nuclear periphery of HDACi-treated cells. After TSA and NaBt treatment, the HP1 proteins were repositioned more internally in the nucleus, being closely associated with interchromatin compartments, while centromeric heterochromatin was relocated closer to the nuclear periphery. These findings strongly suggest dissociation of HP1 proteins from peripherally located centromeres in a hyperacetylated and H3(K4) dimethylated environment. We conclude that inhibition of histone deacetylases caused dynamic reorganization of chromatin in parallel with changes in its epigenetic modifications.
- MeSH
- apoptóza účinky léků MeSH
- buněčné jádro účinky léků enzymologie genetika metabolismus MeSH
- buněčné linie MeSH
- buněčný cyklus účinky léků MeSH
- buňky HT-29 MeSH
- chromatin metabolismus MeSH
- chromozomální proteiny, nehistonové antagonisté a inhibitory metabolismus MeSH
- histondeacetylasy metabolismus MeSH
- histony metabolismus MeSH
- homolog proteinu s chromoboxem 5 MeSH
- inhibitory enzymů farmakologie MeSH
- inhibitory histondeacetylas * MeSH
- interfáze účinky léků MeSH
- kyselina máselná farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- lidé MeSH
- malobuněčný karcinom enzymologie metabolismus patologie MeSH
- nádorové buněčné linie MeSH
- nádory plic enzymologie metabolismus patologie MeSH
- nádory tračníku enzymologie metabolismus patologie MeSH
- plod MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chromatin MeSH
- chromozomální proteiny, nehistonové MeSH
- histondeacetylasy MeSH
- histony MeSH
- homolog proteinu s chromoboxem 5 MeSH
- inhibitory enzymů MeSH
- inhibitory histondeacetylas * MeSH
- kyselina máselná MeSH
- kyseliny hydroxamové MeSH
- trichostatin A MeSH Prohlížeč
