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Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts
Oncogenesis ( IF 5.9 ) Pub Date : 2020-11-09 , DOI: 10.1038/s41389-020-00285-9
Pawan Noel , Shaimaa Hussein , Serina Ng , Corina E. Antal , Wei Lin , Emily Rodela , Priscilla Delgado , Sanna Naveed , Michael Downes , Yin Lin , Ronald M. Evans , Daniel D. Von Hoff , Haiyong Han

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.



中文翻译:

雷公藤甲素靶向胰腺癌细胞和与癌症相关的成纤维细胞中的超增强网络

胰腺导管腺癌(PDAC)的肿瘤微环境高度异质,纤维化和血管不足,以广泛的异型增生为特征,并由肿瘤细胞,与癌症相关的成纤维细胞(CAF)和其他基质细胞维持。迫切需要确定和发展不仅靶向肿瘤细胞而且还可以调节基质细胞的治疗策略。越来越多的研究暗示了被称为超级增强子(SE)的调节性DNA元素在维持正常细胞和癌细胞中特定于细胞类型的基因表达网络中的作用。我们使用染色质激活标记,首先将SE网络映射到胰腺CAF和上皮肿瘤细胞中,发现它们具有不同的SE谱。接下来,我们探讨了雷公藤甲素(TPL)(一种具有抗肿瘤活性的天然化合物)的作用,在调制PDAC中特定于细胞类型的SE签名的情况下。我们发现TPL对胰腺肿瘤细胞和CAF均具有细胞毒性,它以导致mRNA两种细胞类型中与SE相关的基因(例如,BRD4,MYC,RNA Pol II和胶原1)下调的方式破坏了SE。和蛋白质水平。我们的观察结果表明,TPL充当SE的互动剂,并可能通过SE破坏来引发其抗肿瘤活性,从而重新编程PDAC中的细胞串扰和信号传导。根据我们的发现,使用SE调节化合物(例如TPL)对表观遗传进行转录调控重编程可能为胰腺癌患者的有效治疗选择提供手段。在mRNA和蛋白质水平上,两种细胞类型均会导致SE相关基因(例如BRD4,MYC,RNA Pol II和胶原1)的下调,从而破坏SE。我们的观察结果表明,TPL充当SE的互动剂,并可能通过SE破坏来引发其抗肿瘤活性,从而重新编程PDAC中的细胞串扰和信号传导。根据我们的发现,使用SE调节化合物(例如TPL)对表观遗传进行转录调控重编程可能为胰腺癌患者的有效治疗选择提供手段。在mRNA和蛋白质水平上,两种细胞类型均会导致SE相关基因(例如BRD4,MYC,RNA Pol II和胶原1)的下调,从而破坏SE。我们的观察结果表明,TPL充当SE的互动剂,并可能通过SE破坏来引发其抗肿瘤活性,从而重新编程PDAC中的细胞串扰和信号传导。根据我们的发现,使用SE调节化合物(例如TPL)对表观遗传进行转录调控重编程可能为胰腺癌患者的有效治疗选择提供手段。我们的观察结果表明,TPL充当SE的互动剂,并可能通过SE破坏来引发其抗肿瘤活性,从而重新编程PDAC中的细胞串扰和信号传导。根据我们的发现,使用SE调节化合物(例如TPL)对表观遗传进行转录调控重编程可能为胰腺癌患者的有效治疗选择提供手段。我们的观察结果表明,TPL充当SE的互动剂,并可能通过SE破坏来引发其抗肿瘤活性,从而重新编程PDAC中的细胞串扰和信号传导。根据我们的发现,使用SE调节化合物(例如TPL)对表观遗传进行转录调控重编程可能为胰腺癌患者的有效治疗选择提供手段。

更新日期:2020-11-12
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