Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2019 Sep 15;79(18):4599-4611. doi: 10.1158/0008-5472.CAN-19-0215. Epub 2019 Jul 29.
Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity and . In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. SIGNIFICANCE: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.
化学耐药性是由基因组中独特的调控网络驱动的，这些网络与癌症发展所必需的网络不同。在这里，我们研究了增强子元件对卵巢癌顺铂耐药性的贡献。对多种化学耐药性细胞模型的表观基因组分析确定了独特的远端增强子、超级增强子 (SE) 及其基因靶标，这些靶标协调并维持卵巢癌中铂耐药状态的转录程序。通过小分子表观遗传抑制剂抑制远端增强子可抑制其靶基因的表达，并恢复顺铂敏感性。除了已知的化学耐药性驱动因素外，我们的研究结果还确定了 SOX9 作为关键 SE 调节转录因子，在卵巢癌获得和维持化学耐药状态中发挥关键作用。这里提出的方法和发现表明，整合分析表观基因组和转录组程序可以确定癌症中可靶向的化学耐药关键驱动因素。意义：对铂敏感和耐药卵巢系进行全基因组表观基因组和转录组综合分析，确定了关键的远端调控区域和相关的主调控转录因子，这些区域和转录因子可以被小分子表观遗传抑制剂靶向。
