Perturbations in 3D genome organization can promote acquired drug resistance
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 ac...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723011361 |
| _version_ | 1797677680696492032 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Anna G. Manjón |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T22:48:47Z |
| format | Article |
| id | doaj.art-7a246652a6144b62a928cb9cb12c35f2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T22:48:47Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7a246652a6144b62a928cb9cb12c35f22023-09-22T04:38:33ZengElsevierCell Reports2211-12472023-10-014210113124Perturbations in 3D genome organization can promote acquired drug resistanceAnna G. Manjón0Stefano Giustino Manzo1Stefan Prekovic2Leon Potgeter3Tom van Schaik4Ning Qing Liu5Koen Flach6Daniel Peric-Hupkes7Stacey Joosten8Hans Teunissen9Anoek Friskes10Mila Ilic11Dorine Hintzen12Vinícius H. Franceschini-Santos13Wilbert Zwart14Elzo de Wit15Bas van Steensel16René H. Medema17Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, 20133 Milan, ItalyOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, 3584 CX Utrecht, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsDivision of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Department of Hematology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the NetherlandsDivision of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsDivision of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsDivision of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the NetherlandsOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Corresponding authorOncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723011361CP: Molecular biology |
| spellingShingle | 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 Perturbations in 3D genome organization can promote acquired drug resistance Cell Reports CP: Molecular biology |
| title | Perturbations in 3D genome organization can promote acquired drug resistance |
| title_full | Perturbations in 3D genome organization can promote acquired drug resistance |
| title_fullStr | Perturbations in 3D genome organization can promote acquired drug resistance |
| title_full_unstemmed | Perturbations in 3D genome organization can promote acquired drug resistance |
| title_short | Perturbations in 3D genome organization can promote acquired drug resistance |
| title_sort | perturbations in 3d genome organization can promote acquired drug resistance |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723011361 |
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