G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer cells
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background:
Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of
drug treatment. In ovarian cancers, epigenetically driven resistance is thought to be responsible for
many late-stage patient deaths. DNA secondary structures called G-quadruplex (G4) are emerging as
potential epigenetic marks of relevance to cancer evolution, but their prevalence and distribution in
ovarian cancer models has never been investigated before.
Results:
Here, we describe the first investigation of the role of G4s in the epigenetic regulation of drug-resistant
ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant
cell lines, we find that increased G4 accumulation is associated with enhanced transcription of
signalling pathways previously established to promote drug-resistant states, including genes involved
in the epithelial to mesenchymal transition and WNT signalling. In contrast to previous studies, the
expression-enhancing effects of G4s are not found at gene promoters, but intergenic and intronic
regions, indicating that G4s can promote long-range transcriptional regulation in drug-resistant cells.
Furthermore, we discover that clusters of G4s (super-G4s) are associated with particularly high levels
of transcriptional enhancement thatsurpass the effects of super-enhancers, which act as well-established
regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules
results in significant down-regulation of pathways associated with drug-resistance, resulting in
resensitisation of resistant cells to chemotherapy agents.
Conclusions:
These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug resistant cells and represent a promising target to treat drug-tolerant ovarian cancer.
Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of
drug treatment. In ovarian cancers, epigenetically driven resistance is thought to be responsible for
many late-stage patient deaths. DNA secondary structures called G-quadruplex (G4) are emerging as
potential epigenetic marks of relevance to cancer evolution, but their prevalence and distribution in
ovarian cancer models has never been investigated before.
Results:
Here, we describe the first investigation of the role of G4s in the epigenetic regulation of drug-resistant
ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant
cell lines, we find that increased G4 accumulation is associated with enhanced transcription of
signalling pathways previously established to promote drug-resistant states, including genes involved
in the epithelial to mesenchymal transition and WNT signalling. In contrast to previous studies, the
expression-enhancing effects of G4s are not found at gene promoters, but intergenic and intronic
regions, indicating that G4s can promote long-range transcriptional regulation in drug-resistant cells.
Furthermore, we discover that clusters of G4s (super-G4s) are associated with particularly high levels
of transcriptional enhancement thatsurpass the effects of super-enhancers, which act as well-established
regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules
results in significant down-regulation of pathways associated with drug-resistance, resulting in
resensitisation of resistant cells to chemotherapy agents.
Conclusions:
These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug resistant cells and represent a promising target to treat drug-tolerant ovarian cancer.
Date Issued
2025-07-12
Date Acceptance
2025-06-16
Citation
Genome Biology, 2025, 26
ISSN
1474-7596
Publisher
BMC
Journal / Book Title
Genome Biology
Volume
26
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
License URL
Publication Status
Published
Article Number
ARTN 183