Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition
Abstract Background Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could signific...
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03294-x |
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| author | Mie K. Jakobsen Sofie Traynor Aaraby Y. Nielsen Christina Dahl Mette Staehr Simon T. Jakobsen Maria S. Madsen Rasmus Siersbaek Mikkel G. Terp Josefine B. Jensen Christina B. Pedersen Anup Shrestha Jonathan R. Brewer Pascal H. G. Duijf Odd L. Gammelgaard Henrik J. Ditzel Alexei F. Kirkin Per Guldberg Morten F. Gjerstorff |
| author_facet | Mie K. Jakobsen Sofie Traynor Aaraby Y. Nielsen Christina Dahl Mette Staehr Simon T. Jakobsen Maria S. Madsen Rasmus Siersbaek Mikkel G. Terp Josefine B. Jensen Christina B. Pedersen Anup Shrestha Jonathan R. Brewer Pascal H. G. Duijf Odd L. Gammelgaard Henrik J. Ditzel Alexei F. Kirkin Per Guldberg Morten F. Gjerstorff |
| author_sort | Mie K. Jakobsen |
| collection | DOAJ |
| description | Abstract Background Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited. Methods In this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level. The analysis was performed on breast cancer patient-derived xenograft tumors and cell lines, employing a comprehensive set of techniques, including targeted single-cell mRNA sequencing. Mechanistic insights were further gained through DNA methylation profiling and chromatin structure analysis. Results We show that breast cancer tumors and cell cultures exhibit a highly heterogenous response to DNA methyltransferase inhibitors, persisting even under high drug concentrations and efficient DNA methyltransferase depletion. The observed variability in response to DNA methyltransferase inhibitors was independent of cancer-associated aberrations and clonal genetic diversity. Instead, these variations were attributed to stochastic demethylation of regulatory CpG sites and the DNA methylation-independent suppressive function of histone deacetylases. Conclusions Our findings point to intratumoral heterogeneity as a limiting factor in the use of DNA methyltransferase inhibitors as single agents in treatment of solid cancers and highlight histone deacetylase inhibitors as essential partners to DNA methyltransferase inhibitors in the clinic. |
| format | Article |
| id | doaj-art-d76c784c81e6498d9088e90f7f0be147 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-d76c784c81e6498d9088e90f7f0be1472025-01-26T12:57:55ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111510.1186/s13046-025-03294-xStochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibitionMie K. Jakobsen0Sofie Traynor1Aaraby Y. Nielsen2Christina Dahl3Mette Staehr4Simon T. Jakobsen5Maria S. Madsen6Rasmus Siersbaek7Mikkel G. Terp8Josefine B. Jensen9Christina B. Pedersen10Anup Shrestha11Jonathan R. Brewer12Pascal H. G. Duijf13Odd L. Gammelgaard14Henrik J. Ditzel15Alexei F. Kirkin16Per Guldberg17Morten F. Gjerstorff18Department of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDanish Cancer InstituteDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkCentre for Cancer Biology, Clinical and Health Sciences, University of South Australia & SA PathologyDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkCytovac A/SDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer Research, Institute of Molecular Medicine, University of Southern DenmarkAbstract Background Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited. Methods In this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level. The analysis was performed on breast cancer patient-derived xenograft tumors and cell lines, employing a comprehensive set of techniques, including targeted single-cell mRNA sequencing. Mechanistic insights were further gained through DNA methylation profiling and chromatin structure analysis. Results We show that breast cancer tumors and cell cultures exhibit a highly heterogenous response to DNA methyltransferase inhibitors, persisting even under high drug concentrations and efficient DNA methyltransferase depletion. The observed variability in response to DNA methyltransferase inhibitors was independent of cancer-associated aberrations and clonal genetic diversity. Instead, these variations were attributed to stochastic demethylation of regulatory CpG sites and the DNA methylation-independent suppressive function of histone deacetylases. Conclusions Our findings point to intratumoral heterogeneity as a limiting factor in the use of DNA methyltransferase inhibitors as single agents in treatment of solid cancers and highlight histone deacetylase inhibitors as essential partners to DNA methyltransferase inhibitors in the clinic.https://doi.org/10.1186/s13046-025-03294-xDNA methylationDNA methyltransferase inhibitorCancer/testis antigen. |
| spellingShingle | Mie K. Jakobsen Sofie Traynor Aaraby Y. Nielsen Christina Dahl Mette Staehr Simon T. Jakobsen Maria S. Madsen Rasmus Siersbaek Mikkel G. Terp Josefine B. Jensen Christina B. Pedersen Anup Shrestha Jonathan R. Brewer Pascal H. G. Duijf Odd L. Gammelgaard Henrik J. Ditzel Alexei F. Kirkin Per Guldberg Morten F. Gjerstorff Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition Journal of Experimental & Clinical Cancer Research DNA methylation DNA methyltransferase inhibitor Cancer/testis antigen. |
| title | Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition |
| title_full | Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition |
| title_fullStr | Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition |
| title_full_unstemmed | Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition |
| title_short | Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition |
| title_sort | stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological dna methyltransferase inhibition |
| topic | DNA methylation DNA methyltransferase inhibitor Cancer/testis antigen. |
| url | https://doi.org/10.1186/s13046-025-03294-x |
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