DNMT and EZH2 inhibitors synergize for gene activation in hepatocellular carcinoma cells.
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PROVIDER: PRJNA836561 | ENA |
REPOSITORIES: ENA
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Project description:DNMT and EZH2 inhibitors synergize for gene activation in hepatocellular carcinoma cells [RNA-seq]
| PRJNA836565 | ENA
Project description:DNMT and EZH2 inhibitors synergize for gene activation in hepatocellular carcinoma cells [methylation array]
| PRJNA836566 | ENA
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with cases increasing dramatically in the USA. Developing more effective targeted therapies for HCC is an urgent need. The FDA-approved DNA methyltransferase inhibitors (DNMTis) 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2’-deoxycytidine (5-aza-CdR, Decitabine) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, the clinical efficacies of DNMTis are still limited, in part due to an “epigenetic switch” mechanism, in which a large group of genes demethylated by DNMTi treatment remain silenced by Polycomb Repressive Complex 2 (PRC2) occupancy. Overexpression of PRC2 subunits, especially EZH2, is correlated with poor patient survivor in HCC. In this study, we tested the combination of 5-Aza-CdR and the EZH2 inhibitor (EZH2i) GSK-126 in human HCC cell lines (SNU398, HepG2, and SNU475) on DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all cell lines showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently silenced genes. The increased number of up-regulated genes, including tumor suppressors, were correlated with prolonged anti-proliferation effects and nucleosome accessibility but negatively correlated with gene promoter DNA methylation. Detailed epigenome analyses reveal a mechanistic rationale in which the combination treatment of 5-aza-CdR with an EZH2 inhibitor (EZH2i) activates demethylated promoters that are repressed by PRC2 occupancy. Furthermore, about 13.6% to 31% of genes down-regulated by DNA methylation in primary HCC tumors can be reactivated through this combination treatment scheme in vitro. Finally, combination treatment also exacerbates viral mimicry activation as well as leukocyte, lymphocyte and T cell mediated immunity, while most those genes or pathways were downregulated in over 50% of primary HCC tumors in TCGA dataset. Conclusion: we have linked the anti-tumor effects of DNMTi and EZH2i combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.
2022-10-19 | GSE202560 | GEO
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with cases increasing dramatically in the USA. Developing more effective targeted therapies for HCC is an urgent need. The FDA-approved DNA methyltransferase inhibitors (DNMTis) 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2’-deoxycytidine (5-aza-CdR, Decitabine) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, the clinical efficacies of DNMTis are still limited, in part due to an “epigenetic switch” mechanism, in which a large group of genes demethylated by DNMTi treatment remain silenced by Polycomb Repressive Complex 2 (PRC2) occupancy. Overexpression of PRC2 subunits, especially EZH2, is correlated with poor patient survivor in HCC. In this study, we tested the combination of 5-Aza-CdR and the EZH2 inhibitor (EZH2i) GSK-126 in human HCC cell lines (SNU398, HepG2, and SNU475) on DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all cell lines showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently silenced genes. The increased number of up-regulated genes, including tumor suppressors, were correlated with prolonged anti-proliferation effects and nucleosome accessibility but negatively correlated with gene promoter DNA methylation. Detailed epigenome analyses reveal a mechanistic rationale in which the combination treatment of 5-aza-CdR with an EZH2 inhibitor (EZH2i) activates demethylated promoters that are repressed by PRC2 occupancy. Furthermore, about 13.6% to 31% of genes down-regulated by DNA methylation in primary HCC tumors can be reactivated through this combination treatment scheme in vitro. Finally, combination treatment also exacerbates viral mimicry activation as well as leukocyte, lymphocyte and T cell mediated immunity, while most those genes or pathways were downregulated in over 50% of primary HCC tumors in TCGA dataset. Conclusion: we have linked the anti-tumor effects of DNMTi and EZH2i combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.
2022-10-19 | GSE202559 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-19 | GSE202561 | GEO
Project description:Immunotherapies targeting cancer-specific immunogenic neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies could synergize with immunotherapies, mediating the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here we use RNA sequencing from cancer cells treated with DNMT and/or HDAC inhibitors, to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polA+ transcripts (TINPATs), encoding for 61,426 novel open reading frames. We further demonstrate, using human leukocyte antigen immunopeptidomics, the existence of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We demonstrated the potential of the identified t-neoepitopes to elicit an immunogenic T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48 h and /96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.
2023-09-13 | PXD035748 | Pride
Project description:Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving Calcium-Calcineurin-NFAT signaling
| PRJNA996119 | ENA
Project description:DNA methyltransferase inhibitors (DNMTi) are FDA-approved for various hematological malignancies but have limited efficacy in solid tumors. DNA hypomethylation with these drugs is associated with elevated lysine 27 tri-methylation on histone H3 (H3K27me3). We hypothesized that this EZH2-dependent repressive mark limits the full potential of DNMTi. Here, we show in cell line and tumoroid models of colorectal cancer, that low-dose DNMTi sensitizes cells to selective EZH2 inhibitors (EZH2i) that have limited single agent toxicity, and that EZH2i enhances DNMTi-driven molecular and therapeutic effects. Through integrative epigenomic analyses, we reveal that DNMTi induces H3K27me3 accumulation at genomic regions poised with EZH2. Unexpectedly, combined treatment alters the epigenome landscape to promote transcriptional upregulation of the Calcium-Calcineurin-NFAT signaling pathway. Blocking this pathway limits the transcriptional activating effects of the drug combination, including expression of transposable elements and innate immune response genes within a viral defense pathway. Consistently, we demonstrate positive correlations between DNMTi- and viral infection-associated transcription profiles and Calcium signal activation in colon cancer patient samples. Collectively, our study demonstrates that compensatory EZH2 activity following DNA hypomethylation presents a barrier to the therapeutic action of DNMTi in colon cancer, reveals a new application of EZH2i beyond cancers associated with PRC2 hyperactivity, and links Calcium-Calcineurin-NFAT signaling to epigenetic therapy-induced viral mimicry.
2024-02-26 | GSE237553 | GEO
Project description:Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving Calcium-Calcineurin-NFAT signaling [EPIC]
| PRJNA995625 | ENA
Project description:DNA methyltransferase inhibitors (DNMTi) are FDA-approved for various hematological malignancies but have limited efficacy in solid tumors. DNA hypomethylation with these drugs is associated with elevated lysine 27 tri-methylation on histone H3 (H3K27me3). We hypothesized that this EZH2-dependent repressive mark limits the full potential of DNMTi. Here, we show in cell line and tumoroid models of colorectal cancer, that low-dose DNMTi sensitizes cells to selective EZH2 inhibitors (EZH2i) that have limited single agent toxicity, and that EZH2i enhances DNMTi-driven molecular and therapeutic effects. Through integrative epigenomic analyses, we reveal that DNMTi induces H3K27me3 accumulation at genomic regions poised with EZH2. Unexpectedly, combined treatment alters the epigenome landscape to promote transcriptional upregulation of the Calcium-Calcineurin-NFAT signaling pathway. Blocking this pathway limits the transcriptional activating effects of the drug combination, including expression of transposable elements and innate immune response genes within a viral defense pathway. Consistently, we demonstrate positive correlations between DNMTi- and viral infection-associated transcription profiles and Calcium signal activation in colon cancer patient samples. Collectively, our study demonstrates that compensatory EZH2 activity following DNA hypomethylation presents a barrier to the therapeutic action of DNMTi in colon cancer, reveals a new application of EZH2i beyond cancers associated with PRC2 hyperactivity, and links Calcium-Calcineurin-NFAT signaling to epigenetic therapy-induced viral mimicry.
2024-02-26 | GSE236897 | GEO