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The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential

Authors
 SangWun Kim  ;  Reyhaneh Lahmy  ;  Chelsea Riha  ;  Challeng Yang  ;  Brad L. Jakubison  ;  Jaco van Niekerk  ;  Claudio Staub  ;  Yifan Wu  ;  Keith Gates  ;  Duc Si Dong  ;  Stephen F. Konieczny  ;  Pamela Itkin-Ansari 
Citation
 Pancreas, Vol.44(5) : 718-727, 2015 
Journal Title
 Pancreas 
ISSN
 0885-3177 
Issue Date
2015
Abstract
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) initiates from quiescent acinar cells that attain a Kras mutation, lose signaling from basic helix-loop-helix (bHLH) transcription factors, undergo acinar-ductal metaplasia, and rapidly acquire increased growth potential. We queried whether PDA cells can be reprogrammed to revert to their original quiescent acinar cell state by shifting key transcription programs. METHODS: Human PDA cell lines were engineered to express an inducible form of the bHLH protein E47. Gene expression, growth, and functional studies were investigated using microarray, quantitative polymerase chain reaction, immunoblots, immunohistochemistry, small interfering RNA, chromatin immunoprecipitation analyses, and cell transplantation into mice. RESULTS: In human PDA cells, E47 activity triggers stable G0/G1 arrest, which requires the cyclin-dependent kinase inhibitor p21 and the stress response protein TP53INP1. Concurrently, E47 induces high level expression of acinar digestive enzymes and feed forward activation of the acinar maturation network regulated by the bHLH factor MIST1. Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis. CONCLUSIONS: Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential. Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140670
DOI
10.1097/MPA.0000000000000328
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실)
Yonsei Authors
김상운(Kim, Sang Wun)
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