| Autor: |
Anna G. Manjón, Stefano Giustino Manzo, Stefan Prekovic, Leon Potgeter, Tom van Schaik, Ning Qing Liu, Koen Flach, Daniel Peric-Hupkes, Stacey Joosten, Hans Teunissen, Anoek Friskes, Mila Ilic, Dorine Hintzen, Vinícius H. Franceschini-Santos, Wilbert Zwart, Elzo de Wit, Bas van Steensel, René H. Medema |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 42, Iss 10, Pp 113124- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.113124 |
| Popis: |
Summary: Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the ABCB1 gene, encoding for the multidrug transporter P-gP. Here, we investigate how the ABCB1 gene is derepressed. ABCB1 activation is associated with reduced H3K9 trimethylation, increased H3K27 acetylation, and ABCB1 displacement from the nuclear lamina. While altering DNA methylation and H3K27 methylation had no major impact on ABCB1 expression, nor did it promote resistance, disrupting the nuclear lamina component Lamin B Receptor did promote the acquisition of a Taxol-resistant phenotype in a subset of cells. CRISPRa-mediated gene activation supported the notion that lamina dissociation influences ABCB1 derepression. We propose a model in which nuclear lamina dissociation of a repressed gene allows for its activation, implying that deregulation of the 3D genome topology could play an important role in tumor evolution and the acquisition of drug resistance. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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