PMID- 30010625
OWN - NLM
STAT- MEDLINE
DCOM- 20190910
LR  - 20240102
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 128
IP  - 8
DP  - 2018 Aug 1
TI  - The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis.
PG  - 3475-3489
LID - 94287 [pii]
LID - 10.1172/JCI94287 [doi]
AB  - Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% 
      of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 
      inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and 
      that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in 
      pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated 
      from acinar cells remains elusive. Here, we found that exclusive elimination of 
      Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the 
      formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 
      mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 
      bound to regions of the Sox9 promoter to regulate its expression and was critical 
      for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and 
      enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted 
      ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated 
      phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a 
      dual recombinase system resulted in regression of the lesions in mice. Finally, 
      BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 
      is critical for PanIN initiation and progression through positive regulation of 
      SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
FAU - Tsuda, Motoyuki
AU  - Tsuda M
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Fukuda, Akihisa
AU  - Fukuda A
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Roy, Nilotpal
AU  - Roy N
AD  - Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA.
FAU - Hiramatsu, Yukiko
AU  - Hiramatsu Y
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Leonhardt, Laura
AU  - Leonhardt L
AD  - Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA.
FAU - Kakiuchi, Nobuyuki
AU  - Kakiuchi N
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
AD  - Department of Pathology and Tumor Biology, Kyoto University Graduate School of 
      Medicine, Kyoto, Japan.
FAU - Hoyer, Kaja
AU  - Hoyer K
AD  - Department of Pathology and Tumor Biology, Kyoto University Graduate School of 
      Medicine, Kyoto, Japan.
AD  - Hematology, Oncology and Tumorimmunology, Charite-Universitatsmedizin Berlin, 
      Berlin, Germany.
FAU - Ogawa, Satoshi
AU  - Ogawa S
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Goto, Norihiro
AU  - Goto N
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Ikuta, Kozo
AU  - Ikuta K
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Kimura, Yoshito
AU  - Kimura Y
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Matsumoto, Yoshihide
AU  - Matsumoto Y
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Takada, Yutaka
AU  - Takada Y
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Yoshioka, Takuto
AU  - Yoshioka T
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Maruno, Takahisa
AU  - Maruno T
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Yamaga, Yuichi
AU  - Yamaga Y
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
FAU - Kim, Grace E
AU  - Kim GE
AD  - Department of Pathology, UCSF, San Francisco, California, USA.
FAU - Akiyama, Haruhiko
AU  - Akiyama H
AD  - Department of Orthopaedics, Gifu University, Gifu, Japan.
FAU - Ogawa, Seishi
AU  - Ogawa S
AD  - Department of Pathology and Tumor Biology, Kyoto University Graduate School of 
      Medicine, Kyoto, Japan.
FAU - Wright, Christopher V
AU  - Wright CV
AD  - Program in Developmental Biology and Department of Cell and Developmental 
      Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
FAU - Saur, Dieter
AU  - Saur D
AD  - Department of Internal Medicine II, Klinikum Rechts der Isar, Technische 
      Universitat Munchen, Munich, Germany.
FAU - Takaori, Kyoichi
AU  - Takaori K
AD  - Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of 
      Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
FAU - Uemoto, Shinji
AU  - Uemoto S
AD  - Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of 
      Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
FAU - Hebrok, Matthias
AU  - Hebrok M
AD  - Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA.
FAU - Chiba, Tsutomu
AU  - Chiba T
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
AD  - Kansai Electric Power Hospital, Osaka, Japan.
FAU - Seno, Hiroshi
AU  - Seno H
AD  - Department of Gastroenterology and Hepatology, Kyoto University Graduate School 
      of Medicine, Kyoto, Japan.
LA  - eng
GR  - R01 CA172045/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180716
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Nuclear Proteins)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (SOX9 protein, human)
RN  - 0 (Sox9 protein, mouse)
RN  - 0 (TP53 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Trp53 protein, mouse)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 3.6.1.- (SMARCA4 protein, human)
RN  - EC 3.6.1.- (Smarca4 protein, mouse)
RN  - EC 3.6.4.- (DNA Helicases)
SB  - IM
MH  - Animals
MH  - Carcinoma, Pancreatic Ductal/genetics/*metabolism/pathology
MH  - Cell Transformation, Neoplastic/genetics/*metabolism/pathology
MH  - DNA Helicases/*biosynthesis/genetics
MH  - Female
MH  - Gene Expression Regulation
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Nuclear Proteins/*biosynthesis/genetics
MH  - Pancreatic Neoplasms/genetics/*metabolism/pathology
MH  - Response Elements
MH  - SOX9 Transcription Factor/genetics/*metabolism
MH  - *Signal Transduction
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Tumor Suppressor Protein p53/genetics/metabolism
PMC - PMC6063489
OTO - NOTNLM
OT  - Cancer
OT  - Epigenetics
OT  - Gastroenterology
OT  - Mouse models
OT  - Oncology
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2018/07/17 06:00
MHDA- 2019/09/11 06:00
PMCR- 2018/11/01
CRDT- 2018/07/17 06:00
PHST- 2017/03/28 00:00 [received]
PHST- 2018/05/23 00:00 [accepted]
PHST- 2018/07/17 06:00 [pubmed]
PHST- 2019/09/11 06:00 [medline]
PHST- 2018/07/17 06:00 [entrez]
PHST- 2018/11/01 00:00 [pmc-release]
AID - 94287 [pii]
AID - 10.1172/JCI94287 [doi]
PST - ppublish
SO  - J Clin Invest. 2018 Aug 1;128(8):3475-3489. doi: 10.1172/JCI94287. Epub 2018 Jul 
      16.