Pancreatic cancer is one of the most lethal malignant tumors due to a late diagnosis and highly invasion and metastasis. Transforming growth factor-β (TGF-β) signaling plays a vital role in the progression of pancreatic cancer. The delicate activity of TGF-β signaling is particular important for the development of aggression and metastasis which must be fine-tuned. Here, we investigated the role of super-enhancers in regulating the expression of TGF-β signaling pathway in pancreatic cancer. TGFBR2 owns the modification of H3K27Ac around the gene in pancreatic cancer cells. Inhibition of BRD4 by JQ1 robustly blocked the expression of TGFBR2 in a dose dependent manner. We successfully mapped a super-enhancer in TGFBR2 by sgRNA. Deletion of the super-enhancer in TGFBR2 (sgTGFBR2-SEΔ) significantly reduced the expression of TGFBR2 in pancreatic cancer cells. TGF-β-induced p-SMAD2/3 was greatly impaired in TGFBR2 super-enhancer deleted cells. Both migration and EMT induced by TGF-β in pancreatic cancer cells were impaired after deleting the super-enhancer of TGFBR2. Our data suggest a novel molecular mechanism by which a super-enhancer regulates TGFBR2, affecting the activity of TGF-β as well as its function in pancreatic cancer progression.

中文翻译：

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一种超级增强剂通过下调TGFBR2来控制胰腺癌中的TGF-β信号传导。

胰腺癌是由于诊断晚，高度侵袭和转移而引起的最致命的恶性肿瘤之一。转化生长因子-β（TGF-β）信号传导在胰腺癌的进展中起着至关重要的作用。TGF-β信号传导的微妙活性对于必须进行微调的侵略和转移的发展特别重要。在这里，我们研究了胰腺癌中超级增强子在调节TGF-β信号通路表达中的作用。TGFBR2在胰腺癌细胞的基因周围拥有H3K27Ac的修饰。JQ1对BRD4的抑制以剂量依赖性方式强烈阻断了TGFBR2的表达。我们通过sgRNA成功地在TGFBR2中绘制了一个超级增强子。TGFBR2（sgTGFBR2-SEΔ）中的超级增强子的删除显着降低了胰腺癌细胞中TGFBR2的表达。TGF-β诱导的p-SMAD2 / 3在TGFBR2超增强子缺失的细胞中大大受损。删除TGFBR2的超增强剂后，TGF-β诱导的胰腺癌细胞迁移和EMT均受损。我们的数据表明了一种新型分子机制，超级增效剂通过这种分子机制调节TGFBR2，从而影响TGF-β的活性及其在胰腺癌进展中的功能。