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Unknown,Transcriptomics,Genomics,Proteomics

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Calactin - a small molecule induces DNA damage and histione modification in leukemia cells

ABSTRACT: Calactin is a small molecule isolated from the Chinese herb Asclepias curassavica. We found that calactin induced DNA damage, G2/M arrest of cell cycle, and apoptosis. The calactin also increased the H2AX and Chk2 phosphorylation, which resulted in the decrease of Cdc25C and cdk1 expressions, indicating that calactin-induced G2/M arrest. Moreover, we observed that calactin-induced DNA fragmentation (DNA ladder), PARP cleavage, increase in Bad and Bax levels, and decrease in Bcl-2 and Bcl-xl expressions, which results in apoptosis. Furthermore, calactin modulates the histone modification enzymes Aurora B, SET8, MSK1, PCAF, and Gcn5, which result in H3K9, H3K18, and H3K23 acetylation, H3S10 and H3S28 phosphorylation, and H4K20 methylation. Docking results showed that calactin has a tendency to bind the active site of TOP1. This project includes 6 human leukemia K562 cells, 3 for treated 0.15mM calactin for 12hr and the others for control (untreated) samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Sophia Chan

PROVIDER: E-GEOD-20928 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Calactin - a small molecule induces DNA damage and histione modification in leukemia cells

Project description:Calactin is a small molecule isolated from the Chinese herb Asclepias curassavica. We found that calactin induced DNA damage, G2/M arrest of cell cycle, and apoptosis. The calactin also increased the H2AX and Chk2 phosphorylation, which resulted in the decrease of Cdc25C and cdk1 expressions, indicating that calactin-induced G2/M arrest. Moreover, we observed that calactin-induced DNA fragmentation (DNA ladder), PARP cleavage, increase in Bad and Bax levels, and decrease in Bcl-2 and Bcl-xl expressions, which results in apoptosis. Furthermore, calactin modulates the histone modification enzymes Aurora B, SET8, MSK1, PCAF, and Gcn5, which result in H3K9, H3K18, and H3K23 acetylation, H3S10 and H3S28 phosphorylation, and H4K20 methylation. Docking results showed that calactin has a tendency to bind the active site of TOP1.

2011-03-31 | GSE20928 | GEO

Silmitasertib in combination with cabozantinib impairs liver cancer cell cycle progression, induces apoptosis and delays tumor growth in a preclinical model

Project description:The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trial for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70-kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

2024-09-17 | GSE277328 | GEO

Gene expression signatures of MEF2D-silencing hepatocellular carcinoma cells

Project description:Global expression profiles in Huh7 after infection with Lv-shMEF2D and Lv-scrambled, as well as transfection with siRNA-MEF2D and siRNA-control, were compared to investigate the molecular mechanisms involved in MEF2D-mediated regulation of cell cycle. In order to investigate the molecular mechanisms involved in MEF2D-mediated regulation of cell cycle, we assessed gene expression profiles in Huh7 cells after infection with Lv-shMEF2D and Lv-scrambled, as well as transfection with siRNA-MEF2D and siRNA-control, by cDNA microarray. Analysis of global mRNA expression profile indicated a shift toward G2/M arrest in the cells after downregulating MEF2D expression. The genes that inhibit G2/M transition were found to be expressed in high level in MEF2D-downregulated group, as compared with control group. Meanwhile, mRNA abundance of G2/M transition-promoting genes, except CDC2 and CDC25C, was reduced when MEF2D expression was depressed in Huh7 cells

2015-04-07 | E-GEOD-37123 | biostudies-arrayexpress

Transcriptional Profiling of B19 Virus Nonstructure Protein (NS1) transduced CD36+ Erythoid Progenitor Cells (EPCs)

Project description:B19V NS1 is known to be cytotoxic and involved in the pathogenesis of B19V infection. Our previous data demonstrated that NS1 impaired the cell-cycle progression of the CD36+ EPCs by inducing a stable G2 arrest. Microarray analysis was used to identify genes whose expressions were associated with the NS1-induced G2 arrest. A total of 1045 genes displayed a more than 1.5-fold differential expression in the NS1-transduced cells. Out of 1045 differentially expressed genes, 177 were involved in cell-cycle regulation and 51 were involved in the regulation of cell differentiation. Keywords: RNA

2010-11-03 | GSE18906 | GEO

Transcriptional Profiling of B19 Virus Nonstructure Protein (NS1) transduced CD36+ Erythoid Progenitor Cells (EPCs)

2010-11-03 | E-GEOD-18906 | biostudies-arrayexpress

HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway via stimulating MSK1 kinase and suppressing PPP2R2B protein

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. We demonstrated that the transcription factor, HOXC6, was overexpressed in most PDACs, and its inhibition blocked PDAC tumor growth and metastasis. HOXC6 transcriptionally activated the tumor-promoting kinase MSK1. To identify the phosphorylation targets of MSK1 and the mediators of its function in PANC1 cells, we utilized an unbiased TMT10-based phosphoproteomics analysis. To do so, we treated AsPC1 cells with MSK1 inhibitor SB-747651A and performed TMT10-based quantitative phosphoproteomics analysis and identified MSK1 phosphorylation targets.

2023-10-31 | PXD041238 | Pride

HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway via stimulating MSK1 kinase and suppressing PPP2R2B protein

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. We demonstrated that the transcription factor, HOXC6, was overexpressed in most PDACs, and its inhibition blocked PDAC tumor growth and metastasis. HOXC6 transcriptionally activated the tumor-promoting kinase MSK1. To identify the phosphorylation targets of MSK1 and the mediators of its function in AsPC1 cells, we utilized an unbiased TMT10-based phosphoproteomics analysis. To do so, we treated AsPC1 cells with MSK1 inhibitor SB-747651A and performed TMT10-based quantitative phosphoproteomics analysis and identified MSK1 phosphorylation targets.

2023-10-31 | PXD041239 | Pride

Programmable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinase

Project description:We report a synthetic chromatin kinase, by fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase (dCas9-dMSK1). To investigate the role of MSK1 on transcriptional regulation, we explore the different transcriptome between wildtype and MSK1 knockout HEK 293T cell lines by RNA-seq. To test the efficacy of dCas9-dMSK1 at thousands of human promoters in high-throughput and to evaluate if histone phosphorylation could uncover novel mediators of pathological gene expression, we performed a CRISPRa screening assay in A375 cells using the genome wild gRNA library. The enriched gRNAs were measured by Miseq.

2021-01-08 | GSE156381 | GEO

Replication origin mapping of cdc25-22 and Cdc13-Cdc2 cells after G2 block

Project description:Identification of sites of replication initiation by copy number analysis, comparing samples before and after entry into S phase. Experiments were performed in the following strains and conditions: cdc25-22 (temperature-sensitive mutation arrests cells at G2/M for synchrony, otherwise wild type), G2 arrest; Cdc13-Cdc2, G2 arrest.

2018-02-04 | GSE88711 | GEO

Single-cell chromatin accessibility data using scATAC-seq

Project description:Cell-to-cell variation is a universal feature of life that impacts a wide range of biological phenomena, from developmental plasticity to tumor heterogeneity. While recent advances have improved our ability to document cellular phenotypic variation the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of cellular DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells via assay of transposase accessible chromatin sequencing (ATAC-seq). Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single-cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provides insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type specific accessibility variance across 6 cell types. Targeted perturbations of cell cycle or transcription factor signaling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome topological domains de novo, linking single-cell accessibility variation to three-dimensional genome organization. All together, single-cell analysis of DNA accessibility provides new insight into cellular variation of the “regulome.” Profiles of single cell epigenomes, assayed using scATAC-seq, across 8 cell types and 4 targeted cell manipulations. The complete data set contains a total of 1,632 assayed wells.

2015-06-17 | E-GEOD-65360 | biostudies-arrayexpress

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