A super-enhancer controls TGF- β signaling in pancreatic cancer through downregulation of TGFBR2

Xiaolin Zhu; Tingting Zhang; Ye Zhang; Hao Chen; Jianbo Shen; Xinxin Jin; Jinhuan Wei; Erhao Zhang; Mingbing Xiao; Yihui Fan; Renfang Mao; Guoxiong Zhou

doi:10.1016/j.cellsig.2019.109470

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. Epub 2019 Nov 13.

Authors

Xiaolin Zhu¹, Tingting Zhang¹, Ye Zhang², Hao Chen¹, Jianbo Shen¹, Xinxin Jin³, Jinhuan Wei⁴, Erhao Zhang⁴, Mingbing Xiao⁵, Yihui Fan⁶, Renfang Mao⁷, Guoxiong Zhou¹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Receptor, Transforming Growth Factor-beta Type II / metabolism*
Transforming Growth Factor beta / metabolism*

Substances

Transforming Growth Factor beta
Receptor, Transforming Growth Factor-beta Type II
TGFBR2 protein, human