Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, W12 8EE, UK.
Trace Element Laboratory, Charing Cross Hospital, Imperial College NHS Trust, London, UK.
Clin Epigenetics. 2021 Jun 5;13(1):122. doi: 10.1186/s13148-021-01105-6.
Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.
Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.
Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
对 DNA 损伤化疗药物的耐药性导致癌症治疗失败和患者预后不良。我们研究了在对铂类化疗产生临床耐药的情况下，高等级浆液性卵巢癌 (HGSOC) 患者配对的卵巢细胞系中，可接近染色质位点的基因组分布如何发生改变。
耐药株在基因间区域的染色质可接近性发生改变，但在基因启动子处改变较少。这些基因间区域的顺式调控元件簇显示出与相关基因表达改变相关的染色质变化，富集了参与范可尼贫血/BRCA DNA 损伤反应途径的基因。此外，全基因组铂加合物的分布与观察到的染色质变化相关，并将敏感株与耐药株区分开来。在耐药株中，我们观察到基因启动子周围的加合物较少，而基因间区域的加合物较多。
基因表达的基因间调控因子的染色质变化与患者来源的 HGSOC 耐药模型中体内获得的耐药性和 Pt 加合物分布相关。
