Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes
Abstract Derepression of transposable elements (TE) by epigenetic therapy leads to the activation of immune response in cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenet...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08413-0 |
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| author | Divyesh Patel Ville Tiusanen Konsta Karttunen Päivi Pihlajamaa Biswajyoti Sahu |
| author_facet | Divyesh Patel Ville Tiusanen Konsta Karttunen Päivi Pihlajamaa Biswajyoti Sahu |
| author_sort | Divyesh Patel |
| collection | DOAJ |
| description | Abstract Derepression of transposable elements (TE) by epigenetic therapy leads to the activation of immune response in cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenetic drugs to systematically inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal, esophageal, and prostate cancer cells. We show that distinct TE subfamilies are derepressed by inhibition of different CMEs in cell type-specific manner. Co-inhibition of DNMT and HDAC (DNMTi-HDACi) had the most consistent effect across cancer types. Loss of p53 results in stronger TE activation and TE-chimeric transcript expression and this effect is largely mediated by the non-genomic actions of p53. Robust immune response elicited by DNMTi-HDACi is due to induced inverted repeat Alu expression concomitant with reduced ADAR1-mediated Alu RNA editing. Collectively, our systematic analyses provide insights for rational use of epigenetic therapies in distinct cancers. |
| format | Article |
| id | doaj-art-e87a19983aba432c8459d3674f29723c |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e87a19983aba432c8459d3674f29723c2025-08-20T03:45:34ZengNature PortfolioCommunications Biology2399-36422025-07-018111810.1038/s42003-025-08413-0Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymesDivyesh Patel0Ville Tiusanen1Konsta Karttunen2Päivi Pihlajamaa3Biswajyoti Sahu4Applied Tumor Genomics Program, Faculty of Medicine, University of HelsinkiApplied Tumor Genomics Program, Faculty of Medicine, University of HelsinkiApplied Tumor Genomics Program, Faculty of Medicine, University of HelsinkiApplied Tumor Genomics Program, Faculty of Medicine, University of HelsinkiApplied Tumor Genomics Program, Faculty of Medicine, University of HelsinkiAbstract Derepression of transposable elements (TE) by epigenetic therapy leads to the activation of immune response in cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenetic drugs to systematically inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal, esophageal, and prostate cancer cells. We show that distinct TE subfamilies are derepressed by inhibition of different CMEs in cell type-specific manner. Co-inhibition of DNMT and HDAC (DNMTi-HDACi) had the most consistent effect across cancer types. Loss of p53 results in stronger TE activation and TE-chimeric transcript expression and this effect is largely mediated by the non-genomic actions of p53. Robust immune response elicited by DNMTi-HDACi is due to induced inverted repeat Alu expression concomitant with reduced ADAR1-mediated Alu RNA editing. Collectively, our systematic analyses provide insights for rational use of epigenetic therapies in distinct cancers.https://doi.org/10.1038/s42003-025-08413-0 |
| spellingShingle | Divyesh Patel Ville Tiusanen Konsta Karttunen Päivi Pihlajamaa Biswajyoti Sahu Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes Communications Biology |
| title | Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| title_full | Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| title_fullStr | Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| title_full_unstemmed | Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| title_short | Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| title_sort | cancer cell type specific derepression of transposable elements by inhibition of chromatin modifier enzymes |
| url | https://doi.org/10.1038/s42003-025-08413-0 |
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