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| Status |
Public on Feb 26, 2024 |
| Title |
Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving Calcium-Calcineurin-NFAT signaling [siQ-ChIP] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Chromatin Immunoprecipitation for H3K27me3 was performed on HCT116 cells treated with: Vehicle (DMSO), 5'aza-2'deoxycytidine (DAC) 30 nM, DAC 300 nM, Tazemetostat (TAZ) (1 uM), or combination DAC + TAZ for 72 hours.
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| Contributor(s) |
Chomiak AA, Tiedemann RL, Liu Y, Kong X, Cui Y, Thurlow K, Cornett EM, Topper MJ, Baylin SB, Rothbart SB |
| Citation(s) |
38536911 |
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| Submission date |
Jul 10, 2023 |
| Last update date |
Apr 04, 2024 |
| Contact name |
Scott Rothbart |
| E-mail(s) |
scott.rothbart@vai.org
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| Organization name |
Van Andel Research Institute
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| Street address |
333 Bostwick Avenue NE
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| City |
Grand Rapids |
| State/province |
MI |
| ZIP/Postal code |
49503 |
| Country |
USA |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (15)
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| GSM7585015 |
HCT-116 cells, DAC30_H3K27me3_2 |
| GSM7585016 |
HCT-116 cells, DAC300_H3K27me3_1 |
| GSM7585017 |
HCT-116 cells, DAC300_H3K27me3_2 |
| GSM7585018 |
HCT-116 cells, TAZ_H3K27me3_1 |
| GSM7585019 |
HCT-116 cells, TAZ_H3K27me3_2 |
| GSM7585020 |
HCT-116 cells, Combo_H3K27me3_1 |
| GSM7585021 |
HCT-116 cells, Combo_H3K27me3_2 |
| GSM7585022 |
HCT-116 cells, Veh_INPUT |
| GSM7585023 |
HCT-116 cells, DAC30_INPUT |
| GSM7585024 |
HCT-116 cells, DAC300_INPUT |
| GSM7585025 |
HCT-116 cells, TAZ_INPUT |
| GSM7585026 |
HCT-116 cells, Combo_INPUT |
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| This SubSeries is part of SuperSeries: |
| GSE237665 |
Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving Calcium-Calcineurin-NFAT signaling |
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| Relations |
| BioProject |
PRJNA993009 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE236897_DAC300_conserved_peaks_Log2FC_all_regions.bed.gz |
729.2 Kb |
(ftp)(http) |
BED |
| GSE236897_DAC30_conserved_peaks_Log2FC_all_regions.bed.gz |
762.0 Kb |
(ftp)(http) |
BED |
| GSE236897_EPZDAC_conserved_peaks_Log2FC_all_regions.bed.gz |
697.9 Kb |
(ftp)(http) |
BED |
| GSE236897_EPZ_conserved_peaks_Log2FC_all_regions.bed.gz |
697.1 Kb |
(ftp)(http) |
BED |
| GSE236897_RAW.tar |
2.4 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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