PDF(Pubmed)
Abstract：
The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous \'ovarian\' cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors in cis and trans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.
摘要：
转录因子MECOM，PAX8，SOX17和WT1是高级浆液性卵巢癌（HGSC）的候选主调节因子，然而它们在假设的起源组织中的合作作用，输卵管分泌上皮（FTSEC）未知。我们产生了26个表观基因组(CUT&TAG，CUT&RUN,ATAC-seq和HiC）数据集和24个RNA-seq转录因子敲低谱，然后在FTSEC和HGSC模型中进行RNA测序，以定义顺式和反式受这些因子调节的结合位点和基因集。这表明MECOM，PAX8、SOX17和WT1是谱系丰富的，超级增强子相关的主调节因子，其协同DNA结合模式和靶基因在肿瘤发展过程中重新连接。所有四种TFs对于HGSC克隆形成和存活是不可缺少的,但仅PAX8和WT1的耗竭损害FTSEC细胞存活。这四种TF仅在HGSC中而在FTSEC中被转录抑制剂药理学抑制。总的来说，我们的数据表明，肿瘤特异性表观遗传重塑与MECOM密切相关，PAX8、SOX17和WT1活性以及这些转录因子可通过转录抑制剂以肿瘤特异性方式靶向。
