2. Academic Validation
  3. 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

  • Cell Signal. 2020 Feb;66:109470. doi: 10.1016/j.cellsig.2019.109470.
Xiaolin Zhu 1,  Tingting Zhang 1,  Ye Zhang 2,  Hao Chen 1,  Jianbo Shen 1,  Xinxin Jin 3,  Jinhuan Wei 4,  Erhao Zhang 4,  Mingbing Xiao 5,  Yihui Fan 6,  Renfang Mao 7,  Guoxiong Zhou 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, Jiangsu 226001, China.
  • 2 Department of Pathophysiology, School of Medicine, Nantong University, Jiangsu 226001, China.
  • 3 Department of Immunology, School of Medicine, Nantong University, Jiangsu 226001, China.
  • 4 Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu 226001, China.
  • 5 Department of Gastroenterology and Research Center of Clinical Medicine, Affiliated Hospital, Nantong University, Jiangsu, 226001, China.
  • 6 Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu 226001, China; Department of Immunology, School of Medicine, Nantong University, Jiangsu 226001, China.
  • 7 Department of Pathophysiology, School of Medicine, Nantong University, Jiangsu 226001, China; Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu 226001, China. Electronic address: maorenfang@ntu.edu.cn.
PMID: 31730895 DOI: 10.1016/j.cellsig.2019.109470
Abstract

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.

Keywords

Pancreatic cancer; Super-enhancer; TGF-β signaling; TGFBR2; Transcriptional regulation.

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