Simultaneous treatment of castration-resistant prostate cancer cells with the DNA Demethylating Agent Decitabine and S-adenosylmethionine leads to synergistic anti- cancer effects.
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PROVIDER: PRJNA1105942 | ENA |
REPOSITORIES: ENA
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Project description:A general problem of methylating and demethylating agents is a lack of limitation to the promotors of tumor suppressor genes or proto-oncogenes respectively. This may cause adverse consequences. Thus, the question was raised if the simultaneous application of DNA-demethylating agents and S-adenosylmethionine could reverse these effects.
2025-01-02 | GSE266129 | GEO
Project description:array-based analysis of genome-wide DNA methylation changes induced by the demethylating drugs azacytidine and decitabine on HCT116 cells for 24 hours
2010-07-01 | E-MTAB-210 | biostudies-arrayexpress
Project description:Background: In high-grade serous ovarian cancer (HGSOC) intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations, but frequent epigenetic alterations including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated. Aims of this study were to explore how representative HGSOC PDXs are for their corresponding patient tumors methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450K. Further, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the predictive/prognostic value of the identified genes. Results: Only 0.6-1.0% of all analyzed CpGs (388,696 CpGs) changed significantly (p<0.01) during propagation showing that HGSOC PDXs are epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6% of CpG sites in comparison to untreated PDXs (p<0.01, FDR<10%). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g. Src family kinase pathway). Particularly, C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p<0.05) with improved progression free survival and overall survival in HGSOC patients. Conclusion: HGSOC PDXs resemble the global epigenome of patients over many generations, which can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our results encourage future application of PDXs for cancer epigenome studies.
2016-10-10 | GSE81438 | GEO
Project description:The epigenetic regulation, for example, DNA methylation, controls the development and differentiation of both tumor cells and immunocytes. Treatment with DNA demethylating agent (such as decitabine) has shown a dramatic clinical benefit in hematological malignancies and solid tumors. However, the influence of epigenetic therapy on host immune system remains unclear. To investigate the effects of low-dose decitabine therapy on T cells, We collected whole blood samples from two solid tumor patients pre and post low-dose decitabine therapy, and detected the expression profiles of PBMCs.
2016-06-30 | E-GEOD-72686 | biostudies-arrayexpress
Project description:PurposeDecitabine, a promising epi-immunotherapeutic agent has shown clinical responses in solid tumor patients, while the anti-tumor mechanisms were unclear. We aimed to investigate the immunomodulatory effect of decitabine in peripheral T cells.Experimental designWe applied next-generation sequencing to investigate the complementarity-determining region 3 (CDR3) of the TCRβ gene, the diversity of which acts as the prerequisite for the host immune system to recognize the universal foreign antigens. We collected the peripheral blood mononuclear cells (PBMCs) from 4 patients, at baseline and after 2 cycles of low-dose decitabine therapy.ResultsAn increase of the unique productive sequences of the CDR3 of TCRβ was observed in all of the 4 patients after decitabine treatment, which was characterized by a lower abundance of expanded clones and increased TCR diversity compared with before decitabine treatment. Further analysis showed a tendency for CD4 T cells with an increased CD4/CD8 ratio in response to decitabine therapy. In addition, the genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated.ConclusionsThe low-dose DNMT inhibitor decitabine broadens the peripheral T cell repertoire, providing a novel role for the epigenetic modifying agent in anti-tumor immune enhancement.
| S-EPMC5122357 | biostudies-literature
Project description:Array-based analysis of genome-wide DNA methylation changes induced by the demethylating drugs azacytidine and decitabine on HCT116 and HL60 cells for 24 hours
2010-12-01 | E-MTAB-417 | biostudies-arrayexpress
Project description:Decitabine (DEC) has a known DNA demethylating activity but also cause cytotoxicity through DNA damage. The two differing mechanisms of action confound studies investigating the effect of DNA demethylation in cancer treatment. The novel DNA methyltransferase 1 specific inhibitor GSK-3685032 causes loss of DNA methylation without DNA damage and offers the possibility to examine the molecular consequences of global loss of DNA methylation. EM-seq was used to evaluate the DNA demethylating effects of DEC and GSK-3685032 in LOUCY and SUP-T1 cells treated with 10 nM Decitabine for 3 days or 300 nM of GSK-3685032 for 3 and 7 days.
2024-10-13 | E-MTAB-14202 | biostudies-arrayexpress
Project description:Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBCs) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype-specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naive breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in TNBC patients treated with decitabine as a second line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene-specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis (GSEA) of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways in decitabine treated cells. Induced genes included those characterized by the viral mimicry response; however knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients. We used microarrays to determine genome-wide expression changes induced by DNA de-methylating agent decitabine in breast cancer cell lines
2020-06-01 | GSE133987 | GEO
Project description:The epigenetic regulation, for example, DNA methylation, controls the development and differentiation of both tumor cells and immunocytes. Treatment with DNA demethylating agent (such as decitabine) has shown a dramatic clinical benefit in hematological malignancies and solid tumors. However, the influence of epigenetic therapy on host immune system remains unclear.
2016-06-30 | GSE72686 | GEO
Project description:The epigenetic regulation, for example, DNA methylation, controls the development and differentiation of both tumor cells and immunocytes. Treatment with DNA demethylating agent (such as decitabine) has shown a dramatic clinical benefit in hematological malignancies and solid tumors. However, the influence of epigenetic therapy on host immune system remains unclear.
2016-12-01 | GSE80377 | GEO