The role of G-quadruplex DNA in the transcriptional reprogramming of drug-resistant ovarian cancer cells
File(s)
Author(s)
Flint, Gem
Type
Thesis
Abstract
Acquired drug resistance remains a major challenge in the treatment of late-stage ovarian cancer. There are many molecular mechanisms that contribute to the acquisition of resistance, that enable the cancer cells to reduce drug efficacy and evade apoptosis. Of note, epigenetic adaptation plays a crucial role in the development of drug resistance, through mediating changes in the expression of genes implicated in signalling pathways associated with resistance. One emerging epigenetic regulator that has not yet been considered in the context of ovarian cancer drug resistance is the non-canonical DNA structure called G-quadruplexes (G4s). These structures are implicated in transcriptional regulation, either proximally through the enrichment of G4s at oncogene promoters, or distally through the enrichment of G4s at the boundaries of chromatin loops, bringing genomic regulatory elements into proximity. Therefore, it was hypothesised that G4 formation could facilitate epigenetic adaptation, and promote drug resistance, in ovarian cancer. To investigate this, this project employed a multi-layered epigenomics approach in both drug-sensitive and drug-resistant paired ovarian cancer cell lines. The aim was to evaluate the impact of G4 formation on gene expression in the drug-resistant cell lines, relative to changes in chromatin accessibility which is an established regulatory mechanism. It was observed that G4s forming at introns and intergenic regions had a greatly significant transcriptomic impact, compared to a gain in chromatin accessibility at these sites. However, G4s gained in all regions of the drug-resistant cell lines were enriched in pathways associated with acquired drug resistance. Perturbation of the G4s resulted in the significant downregulation of pathways associated with drug resistance and resulted in a partial re-sensitisation to cisplatin. This suggests that G4s are implicated with the epigenetic regulation of drug resistance in ovarian cancer and may represent a valuable therapeutic target to overcome therapy resistance.
Version
Open Access
Date Issued
2025-10-01
Date Awarded
01/01/2026
License URL
Advisor
Di Antonio, Marco
Keun, Hector
Sponsor
Cancer Research UK
Engineering and Physical Science Research Council
Grant Number
EP/S023518/1
CANTAC721\100021
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)