title: The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential.
abstract: OBJECTIVE
  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.
authors.affiliation: From the *Development and Aging Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA; †Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Department of Pediatrics, University of California, San Diego, La Jolla, CA; §Department of Biological Sciences, Center for Cancer Research, the Bindley Bioscience Center, Purdue University, West Lafayette, IN; and ∥Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors.forename: SangWun
authors.initials: S
authors.lastname: Kim
authors.forename: Reyhaneh
authors.initials: R
authors.lastname: Lahmy
authors.forename: Chelsea
authors.initials: C
authors.lastname: Riha
authors.forename: Challeng
authors.initials: C
authors.lastname: Yang
authors.forename: Brad L
authors.initials: BL
authors.lastname: Jakubison
authors.forename: Jaco
authors.initials: J
authors.lastname: van Niekerk
authors.forename: Claudio
authors.initials: C
authors.lastname: Staub
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wu
authors.forename: Keith
authors.initials: K
authors.lastname: Gates
authors.forename: Duc Si
authors.initials: DS
authors.lastname: Dong
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.forename: Pamela
authors.initials: P
authors.lastname: Itkin-Ansari
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D010641:Phenotype; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C407909:TCF3 protein, human