A super-enhancer controls TGF- β signaling in pancreatic cancer through downregulation of TGFBR2
A super-enhancer controls TGF- β signaling in pancreatic cancer through downregulation of TGFBR2
复制标题
超级增强子通过下调 TGFBR2 控制胰腺癌中的 TGF-β 信号传导
DOI：
10.1016/j.cellsig.2019.109470
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发表时间：
2020
影响因子：
4.8
通讯作者：
Guoxiong Zhou
中科院分区：
文献类型：
--
作者：
Xiaolin Zhu;Tingting Zhang;Ye Zhang;Hao Chen;Jianbo Shen;Xinxin Jin;Jinhuan Wei;Erhao Zhang;Mingbing Xiao;Yihui Fan;Renfang Mao;Guoxiong Zhou
胰腺癌因其诊断较晚、侵袭性和转移性高，是最致命的恶性肿瘤之一。转化生长因子-β (TGF-β)信号在胰腺癌的进展中起着至关重要的作用。TGF-β信号的微妙活性对侵袭和转移的发展尤为重要，必须进行微调。在此，我们研究了超增强子在胰腺癌中调控TGF-β信号通路表达的作用。TGFBR2在胰腺癌细胞中具有基因周围的H3K27Ac修饰。JQ1对BRD4的抑制以剂量依赖的方式强有力地阻断TGFBR2的表达。我们成功地通过sgRNA在TGFBR2中定位了一个超级增强子。删除TGFBR2中的超级增强子（sgTGFBR2-SEΔ）可显著降低TGFBR2在胰腺癌细胞中的表达。TGF-β诱导的p-SMAD2/3在TGFBR2超增强子缺失的细胞中显著受损。删除TGFBR2超增强子后，胰腺癌细胞中TGF-β诱导的迁移和EMT均受损。我们的数据提示了一种新的分子机制，通过一种超级增强子调节TGFBR2，影响TGF-β的活性及其在胰腺癌进展中的功能。
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.