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
  • 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: [email protected].
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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