Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA720322 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14139729.fastq.gz | Fastqsanger.gz | |||
| SRR14139730.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description: Not available
| S-EPMC7507826 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-07 | GSE171622 | GEO
Project description:Epigenetic reprogramming using demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a high therapeutic efficacy, despite its small demethylating effect. Here, we aimed to reveal the mechanisms of how such low-dose treatment shows high efficacy by focusing on epigenetic reprograming at the single-cell level. Single-cell RNA-sequencing of HCT116 cells treated with decitabine (DAC) revealed that up-regulated genes were highly variable at the single-cell level. To analyze functional consequences at the single-cell level, DAC-treated HCT116 cells were cloned. While only partial reduction of methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes was observed, depending upon clones. For example, p16 was completely demethylated in the H3-32 clone out of 9 clones, and this clone showed slower proliferation than other clones without demethylation. In addition, in this clone, the fraction of cells with tetraploid became much larger, indicating that cellular senescence was induced. These results showed that epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the high efficacy of low-dose DNA demethylating therapy.
2020-10-02 | GSE149255 | GEO
Project description:Radiotherapy (RT) is a cornerstone of cancer treatment; however, its efficacy is frequently hampered by its adverse effects on normal tissues. By studying the effects of high-dose radiotherapy (HDRT) and low-dose radiotherapy (LDRT), we found that cancer cells adapt distinct responses to these doses to reduce cytotoxicity. Upon HDRT, cancer cells initiate a strong DNA damage response (DDR) to gain resistance through rapid production and/or activation of proteins for cell cycle arrest and DNA damage repair. In contrast, LDRT has a milder effect on the DDR and promotes resistance by triggering the synthesis of new proteins, including those essential for DNA repair and protein damage clearance. We showed that the inhibition of proteasome activity using a proteasome inhibitor (PI) result in the accumulation of damage to both proteins and DNA, leading to the profound death of cancer cells. Mechanistically, LDRT enhances protein synthesis through both increased mTOR signaling and 80S ribosome assembly. On the basis of these findings, we designed a chemoradiotherapy strategy that combines LDTR with PI to treat cancer while minimizing non-targeted toxicity.
2026-02-26 | PXD074928 |
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy.
2012-07-30 | GSE31101 | GEO
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy.
2012-07-30 | GSE28744 | GEO
Project description:Radiotherapy (RT) is a cornerstone of cancer treatment; however, its efficacy is frequently hampered by its adverse effects on normal tissues. By studying the effects of high-dose radiotherapy (HDRT) and low-dose radiotherapy (LDRT), we found that cancer cells adapt distinct responses to these doses to reduce cytotoxicity. Upon HDRT, cancer cells initiate a strong DNA damage response (DDR) to gain resistance through rapid production and/or activation of proteins for cell cycle arrest and DNA damage repair. In contrast, LDRT has a milder effect on the DDR and promotes resistance by triggering the synthesis of new proteins, including those essential for DNA repair and protein damage clearance. We showed that the inhibition of proteasome activity using a proteasome inhibitor (PI) result in the accumulation of damage to both proteins and DNA, leading to the profound death of cancer cells. Mechanistically, LDRT enhances protein synthesis through both increased mTOR signaling and 80S ribosome assembly. On the basis of these findings, we designed a chemoradiotherapy strategy that combines LDTR with PI to treat cancer while minimizing non-targeted toxicity.
2026-02-27 | PXD074982 |
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy. A microarray study using genomic DNA from different DLBCL cell lines before any treatment. Two to four biological replicates by cell line. The HELP data wil be used to find genes hypermethylated in resistant cell lines compared to sensitive cell lines to doxorubicin and other drugs.
2012-07-29 | E-GEOD-31101 | biostudies-arrayexpress
Project description:Low-dose quercetin positively regulates mouse healthspan
| PRJNA545993 | ENA
Project description:Low-Dose Carbon Monoxide Inhibits Cancer Metastasis
| PRJNA727815 | ENA