A super-enhancer controls TGF- β signaling in pancreatic cancer through downregulation of TGFBR2.
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.
['Zhu|Xiaolin|X|', 'Zhang|Tingting|T|', 'Zhang|Ye|Y|', 'Chen|Hao|H|', 'Shen|Jianbo|J|', 'Jin|Xinxin|X|', 'Wei|Jinhuan|J|', 'Zhang|Erhao|E|', 'Xiao|Mingbing|M|', 'Fan|Yihui|Y|', 'Mao|Renfang|R|', 'Zhou|Guoxiong|G|']
D045744:Cell Line, Tumor D015972:Gene Expression Regulation, Neoplastic D006801:Humans D010190:Pancreatic Neoplasms D000077294:Receptor, Transforming Growth Factor-beta Type II D016212:Transforming Growth Factor beta
Super-enhancer Pancreatic cancer TGFBR2 TGF-β signaling Transcriptional regulation