Perturbations in 3D genome organization can promote acquired drug resistance

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113124-113124, Article 113124
• Main Authors: Manjón, Anna G., Manzo, Stefano Giustino, Prekovic, Stefan, Potgeter, Leon, van Schaik, Tom, Liu, Ning Qing, Flach, Koen, Peric-Hupkes, Daniel, Joosten, Stacey, Teunissen, Hans, Friskes, Anoek, Ilic, Mila, Hintzen, Dorine, Franceschini-Santos, Vinícius H., Zwart, Wilbert, de Wit, Elzo, van Steensel, Bas, Medema, René H.
• Format: Article
• Language: English
• Subjects: 3D genome; chromatin; CP: Molecular biology; drug resistance; gene regulation; nuclear lamina
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113124

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. [Display omitted] •Taxol resistance in RPE cells results from ABCB1 gene re-activation•Taxol-resistant cells display altered chromatin marks and NL interactions at the ABCB1 locus•Modifying chromatin marks with inhibitors has limited impact on ABCB1 expression•Loss of LBR facilitates ABCB1 derepression upon Taxol exposure Manjon et al. demonstrate that Taxol resistance in cells arises from ABCB1 gene activation, linked to altered histone modifications and 3D genome topology, especially in NL interactions. Inhibition of repressive chromatin modifiers had no impact on ABCB1 expression, while LBR disruption led to Taxol resistance in a subset of cells.