Perturbations in 3D genome organization can promote acquired drug resistance

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

doi:10.1016/j.celrep.2023.113124

Perturbations in 3D genome organization can promote acquired drug resistance

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	113124
Number of pages	24
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113124
Publication status	Published - 31 Oct 2023

Keywords

Cell Line, Tumor
DNA Methylation/genetics
Drug Resistance, Multiple/genetics
Drug Resistance, Neoplasm/genetics
Humans
Neoplasms/genetics
Paclitaxel/pharmacology
chromatin
gene regulation
CP: Molecular biology
3D genome
nuclear lamina
drug resistance

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10.1016/j.celrep.2023.113124Licence: CC BY-NC-ND

PIIS2211124723011361Final published version, 5.66 MBLicence: CC BY-NC-ND

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Manjón, A. G., Manzo, S. G., Prekovic, S., Potgeter, L., van Schaik, T., Liu, N. Q., Flach, K., Peric-Hupkes, D., Joosten, S., Teunissen, H., Friskes, A., Ilic, M., Hintzen, D., Franceschini-Santos, V. H., Zwart, W., de Wit, E., van Steensel, B., & Medema, R. H. (2023). Perturbations in 3D genome organization can promote acquired drug resistance. Cell Reports, 42(10), Article 113124. https://doi.org/10.1016/j.celrep.2023.113124

@article{589b445aefcb42c0b5b962c6bcec39cb,

title = "Perturbations in 3D genome organization can promote acquired drug resistance",

abstract = "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.",

keywords = "Cell Line, Tumor, DNA Methylation/genetics, Drug Resistance, Multiple/genetics, Drug Resistance, Neoplasm/genetics, Humans, Neoplasms/genetics, Paclitaxel/pharmacology, chromatin, gene regulation, CP: Molecular biology, 3D genome, nuclear lamina, drug resistance",

author = "Manj{\'o}n, {Anna G} and Manzo, {Stefano Giustino} and Stefan Prekovic and Leon Potgeter and {van Schaik}, Tom and Liu, {Ning Qing} and Koen Flach and Daniel Peric-Hupkes and Stacey Joosten and Hans Teunissen and Anoek Friskes and Mila Ilic and Dorine Hintzen and Franceschini-Santos, {Vin{\'i}cius H} and Wilbert Zwart and {de Wit}, Elzo and {van Steensel}, Bas and Medema, {Ren{\'e} H}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

day = "31",

doi = "10.1016/j.celrep.2023.113124",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "10",

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Manjón, AG, Manzo, SG, Prekovic, S, Potgeter, L, van Schaik, T, Liu, NQ, Flach, K, Peric-Hupkes, D, Joosten, S, Teunissen, H, Friskes, A, Ilic, M, Hintzen, D, Franceschini-Santos, VH, Zwart, W, de Wit, E, van Steensel, B & Medema, RH 2023, 'Perturbations in 3D genome organization can promote acquired drug resistance', Cell Reports, vol. 42, no. 10, 113124. https://doi.org/10.1016/j.celrep.2023.113124

TY - JOUR

T1 - Perturbations in 3D genome organization can promote acquired drug resistance

AU - Manjón, Anna G

AU - Manzo, Stefano Giustino

AU - Prekovic, Stefan

AU - Potgeter, Leon

AU - van Schaik, Tom

AU - Liu, Ning Qing

AU - Flach, Koen

AU - Peric-Hupkes, Daniel

AU - Joosten, Stacey

AU - Teunissen, Hans

AU - Friskes, Anoek

AU - Ilic, Mila

AU - Hintzen, Dorine

AU - Franceschini-Santos, Vinícius H

AU - Zwart, Wilbert

AU - de Wit, Elzo

AU - van Steensel, Bas

AU - Medema, René H

PY - 2023/10/31

Y1 - 2023/10/31

N2 - 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.

AB - 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.

KW - Cell Line, Tumor

KW - DNA Methylation/genetics

KW - Drug Resistance, Multiple/genetics

KW - Drug Resistance, Neoplasm/genetics

KW - Humans

KW - Neoplasms/genetics

KW - Paclitaxel/pharmacology

KW - chromatin

KW - gene regulation

KW - CP: Molecular biology

KW - 3D genome

KW - nuclear lamina

KW - drug resistance

UR - http://www.scopus.com/inward/record.url?scp=85171866409&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.113124

DO - 10.1016/j.celrep.2023.113124

M3 - Article

C2 - 37733591

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 113124

ER -

Perturbations in 3D genome organization can promote acquired drug resistance

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