DMSO control and DZNep treated MOLM-14 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30315 | GEO | 2011/07/01
SECONDARY ACCESSION(S): PRJNA143569
REPOSITORIES: GEO
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Project description:We demonstrated that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, induce robust apoptosis in AML cells through increased ROS production and ER stress. We identified a core gene signature including TXNIP, a major redox control molecule which is crucial in DZNep-induced apoptosis. MOLM-14 cells were treated with DMSO and DZNep 2 µM for 24 hours
2011-07-01 | E-GEOD-30315 | biostudies-arrayexpress
Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM.
2011-07-04 | GSE26921 | GEO
Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. Cells were treated with 0.5 μmol/L DZNep for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip® Human Genome U133A Array (Affymetrix) following the manufacturer’s instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.
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Project description:Analysis of DZNep-induced gene expression changes in cultured podocytes. The hypothesis tested in the present study was that DZnep ultimately augments Txnip expression, increasing oxidative stress in podocytes. These results provide important information on the response of podocytes to histone methyltransferase inhibition and a possible mechanism for DZNep action in podocytes.
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Project description:Jeko-1 cells were culture with or without PRC2 inhibitor 3-deazaneplanocin A (DZNep)(1uM) for 72hrs. We used TaqMan® Human MicroRNA Array to quantitate miRNA expression profile regulated by PRC2.
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Project description:Analysis of DZNep-induced gene expression changes in cultured podocytes. The hypothesis tested in the present study was that DZnep ultimately augments Txnip expression, increasing oxidative stress in podocytes. These results provide important information on the response of podocytes to histone methyltransferase inhibition and a possible mechanism for DZNep action in podocytes. Total RNA obtained from cultured podocytes subjected to 48 hours in vitro, with or without DZNep.
2015-12-09 | E-GEOD-60038 | biostudies-arrayexpress
Project description:DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have already been approved by the FDA for the treatment of hematologic malignancies. However, drugs that target the other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit the trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as re-activate silenced genes in cancer cells. This finding opens the door to pharmacological inhibition of histone methylation and we therefore wanted to further study the mechanism of action of 3-deazaneplanocin A in cancer cells. Western blot analysis showed that two other drugs, sinefungin and adenosine-dialdehyde (Adox), have similar effects on the trimethylation H3K27 as 3-deazaneplanocin A and that DZNep is not selective, but globally inhibits histone methylation. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show DZNep acts via a different pathway to 5-aza-2´-deoxycytidine (5-azaCdR), a DNA methyltransferase inhibitor and gives us an interesting insight into how chromatin structure effects gene expression. We also determine the kinetics of gene activation in order to understand if the induced changes were somatically heritable. We have found that upon removal of DZNep, gene expression is reduced to its original state suggesting that there is a homeostatic mechanism which returns the histone modifications to their “ground state” after DZNep treatment. Not only do these studies show the strong need for further development of histone methylation inhibitors but also allow us to better understand how chromatin structure affects gene expression.
2009-03-01 | GSE13733 | GEO
Project description:Jeko-1 cells were culture with or without PRC2 inhibitor 3-deazaneplanocin A (DZNep)(1uM) for 72hrs. We used TaqManM-BM-. Human MicroRNA Array to quantitate miRNA expression profile regulated by PRC2. qPCR miRNA expression profiling.
2012-08-11 | E-GEOD-40019 | biostudies-arrayexpress
Project description:3-deazaneplanocin A (DZNeP) is a promising cancer drug affecting the methylation status of histone lysine residues. To investigate the specificity and mode of action of DZNeP, zebrafish embryos displaying high histone methyltransferase activity were cultured with DZNeP and histone methylation (H3K4me3, H3K9me3, H3K27me3) was mapped by ChIP-chip genome-wide promoter at post-MBT stage (5.3 hpf) . We used a custom 2.1M probe HD promoter array (Nimblegen) for ChIP and input DNA hybridization. Peak detection was done using MA2C with P=10e-4 as cutoff.
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