Robinson Jenna, Flint Gem, Garner Ian, Galli Silvia, Maher Thomas E, Kuimova Marina K, Vilar Ramon, McNeish Iain A, Brown Robert, Keun Hector, Di Antonio Marco
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, London, W12 0BZ, UK.
Institute of Chemical Biology, Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, London, W12 0BZ, UK.
Genome Biol. 2025 Jul 12;26(1):183. doi: 10.1186/s13059-025-03654-y.
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-quadruplexes (G4s) are emerging as potential epigenetic marks of relevance to cancer evolution, but their prevalence and distribution in ovarian cancer models have never been investigated before.
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 that surpass 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 downregulation of pathways associated with drug resistance, resulting in resensitization of resistant cells to chemotherapy agents.
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.
表观遗传进化是癌细胞用于逃避药物治疗效果的一种常见机制。在卵巢癌中，表观遗传驱动的耐药性被认为是许多晚期患者死亡的原因。称为G-四链体（G4s）的DNA二级结构正逐渐成为与癌症进化相关的潜在表观遗传标记，但此前从未研究过它们在卵巢癌模型中的发生率和分布情况。
在此，我们首次描述了G4s在耐药性卵巢癌细胞表观遗传调控中的作用研究。通过对配对的药物敏感和耐药细胞系中的G4s进行全基因组定位，我们发现G4积累增加与先前确定的促进耐药状态的信号通路转录增强有关，包括参与上皮-间质转化和WNT信号传导的基因。与先前的研究不同，G4s的表达增强作用并非在基因启动子处发现，而是在基因间和内含子区域，这表明G4s可以促进耐药细胞中的远程转录调控。此外，我们发现G4s簇（超级G4s）与特别高水平的转录增强相关，这种增强超过了超级增强子的作用，超级增强子在许多癌症中是已确立的调控位点。最后，我们证明用小分子靶向G4s会导致与耐药性相关的信号通路显著下调，从而使耐药细胞对化疗药物重新敏感。
这些发现表明，G4结构对于耐药细胞的表观遗传调控网络至关重要，并且是治疗耐药物性卵巢癌的一个有前景的靶点。
