获得性药物耐药是肿瘤治疗中的一个重要问题。hTERT长生不老、非转化的RPE-1细胞可以通过解抑制编码多药转运蛋白P-gP的ABCB1基因来获得对紫杉醇的耐药性。在这里，我们研究了ABCB1基因如何解抑制。ABCB1的激活与H3K9三甲基化减少、H3K27乙酰化增加以及ABCB1从核膜脱离相关。虽然改变DNA甲基化和H3K27甲基化对ABCB1表达没有重大影响，也没有促进耐药性，但扰乱核膜成分Lamin B Receptor确实促进了一部分细胞获得紫杉醇耐药性表型。CRISPRa介导的基因激活支持了核膜解离影响ABCB1解抑制的观点。我们提出了一个假设模型，即一个被抑制的基因的核膜解离允许其激活，暗示3D基因组拓扑失调可能在肿瘤演化和获得药物耐药性中发挥重要作用。版权所有© 2023 The Authors。由Elsevier Inc.发表，保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.