Satoshi Ogawa1, Akihisa Fukuda2, Yoshihide Matsumoto1, Yuta Hanyu1, Makoto Sono1, Yuichi Fukunaga3, Tomonori Masuda1, Osamu Araki1, Munemasa Nagao1, Takaaki Yoshikawa1, Norihiro Goto1, Yukiko Hiramatsu1, Motoyuki Tsuda1, Takahisa Maruno1, Yuki Nakanishi1, Mohammed S Hussein4, Tatsuaki Tsuruyama5, Kyoichi Takaori6, Shinji Uemoto6, Hiroshi Seno1. 1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 2. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: fukuda26@kuhp.kyoto-u.ac.jp. 3. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. 4. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Internal Medicine, Al-Azhar University, Cairo, Egypt. 5. Clinical Bioresource Center, Kyoto University Hospital, Kyoto, Japan. 6. Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Abstract
BACKGROUND & AIMS: SETDB1, a histone methyltransferase that trimethylates histone H3 on lysine 9, promotes development of several tumor types. We investigated whether SETDB1 contributes to development of pancreatic ductal adenocarcinoma (PDAC). METHODS: We performed studies with Ptf1aCre; KrasG12D; Setdb1f/f, Ptf1aCre; KrasG12D; Trp53f/+; Setdb1f/f, and Ptf1aCre; KrasG12D; Trp53f/f; Setdb1f/f mice to investigate the effects of disruption of Setdb1 in mice with activated KRAS-induced pancreatic tumorigenesis, with heterozygous or homozygous disruption of Trp53. We performed microarray analyses of whole-pancreas tissues from Ptf1aCre; KrasG12D; Setdb1f/f, and Ptf1aCre; KrasG12D mice and compared their gene expression patterns. Chromatin immunoprecipitation assays were performed using acinar cells isolated from pancreata with and without disruption of Setdb1. We used human PDAC cells for SETDB1 knockdown and inhibitor experiments. RESULTS: Loss of SETDB1 from pancreas accelerated formation of premalignant lesions in mice with pancreata that express activated KRAS. Microarray analysis revealed up-regulated expression of genes in the apoptotic pathway and genes regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevented formation of PDACs, concomitant with increased apoptosis and up-regulated expression of Trp53 in mice heterozygous for disruption of Trp53. In contrast, pancreata of mice with homozygous disruption of Trp53 had no increased apoptosis, and PDACs developed. Chromatin immunoprecipitation revealed that SETDB1 bound to the Trp53 promoter to regulate its expression. Expression of an inactivated form of SETDB1 in human PDAC cells with wild-type TP53 resulted in TP53-induced apoptosis. CONCLUSIONS: We found that the histone methyltransferase SETDB1 is required for development of PDACs, induced by activated KRAS, in mice. SETDB1 inhibits apoptosis by regulating expression of p53. SETDB1 might be a therapeutic target for PDACs that retain p53 function.
BACKGROUND & AIMS:SETDB1, a histone methyltransferase that trimethylates histone H3 on lysine 9, promotes development of several tumor types. We investigated whether SETDB1 contributes to development of pancreatic ductal adenocarcinoma (PDAC). METHODS: We performed studies with Ptf1aCre; KrasG12D; Setdb1f/f, Ptf1aCre; KrasG12D; Trp53f/+; Setdb1f/f, and Ptf1aCre; KrasG12D; Trp53f/f; Setdb1f/f mice to investigate the effects of disruption of Setdb1 in mice with activated KRAS-induced pancreatic tumorigenesis, with heterozygous or homozygous disruption of Trp53. We performed microarray analyses of whole-pancreas tissues from Ptf1aCre; KrasG12D; Setdb1f/f, and Ptf1aCre; KrasG12D mice and compared their gene expression patterns. Chromatin immunoprecipitation assays were performed using acinar cells isolated from pancreata with and without disruption of Setdb1. We used human PDAC cells for SETDB1 knockdown and inhibitor experiments. RESULTS: Loss of SETDB1 from pancreas accelerated formation of premalignant lesions in mice with pancreata that express activated KRAS. Microarray analysis revealed up-regulated expression of genes in the apoptotic pathway and genes regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevented formation of PDACs, concomitant with increased apoptosis and up-regulated expression of Trp53 in mice heterozygous for disruption of Trp53. In contrast, pancreata of mice with homozygous disruption of Trp53 had no increased apoptosis, and PDACs developed. Chromatin immunoprecipitation revealed that SETDB1 bound to the Trp53 promoter to regulate its expression. Expression of an inactivated form of SETDB1 in human PDAC cells with wild-type TP53 resulted in TP53-induced apoptosis. CONCLUSIONS: We found that the histone methyltransferase SETDB1 is required for development of PDACs, induced by activated KRAS, in mice. SETDB1 inhibits apoptosis by regulating expression of p53. SETDB1 might be a therapeutic target for PDACs that retain p53 function.
Authors: Evangelina López de Maturana; Juan Antonio Rodríguez; Lola Alonso; Oscar Lao; Esther Molina-Montes; Isabel Adoración Martín-Antoniano; Paulina Gómez-Rubio; Rita Lawlor; Alfredo Carrato; Manuel Hidalgo; Mar Iglesias; Xavier Molero; Matthias Löhr; Christopher Michalski; José Perea; Michael O'Rorke; Victor Manuel Barberà; Adonina Tardón; Antoni Farré; Luís Muñoz-Bellvís; Tanja Crnogorac-Jurcevic; Enrique Domínguez-Muñoz; Thomas Gress; William Greenhalf; Linda Sharp; Luís Arnes; Lluís Cecchini; Joaquim Balsells; Eithne Costello; Lucas Ilzarbe; Jörg Kleeff; Bo Kong; Mirari Márquez; Josefina Mora; Damian O'Driscoll; Aldo Scarpa; Weimin Ye; Jingru Yu; Montserrat García-Closas; Manolis Kogevinas; Nathaniel Rothman; Debra T Silverman; Demetrius Albanes; Alan A Arslan; Laura Beane-Freeman; Paige M Bracci; Paul Brennan; Bas Bueno-de-Mesquita; Julie Buring; Federico Canzian; Margaret Du; Steve Gallinger; J Michael Gaziano; Phyllis J Goodman; Marc Gunter; Loic LeMarchand; Donghui Li; Rachael E Neale; Ulrika Peters; Gloria M Petersen; Harvey A Risch; Maria José Sánchez; Xiao-Ou Shu; Mark D Thornquist; Kala Visvanathan; Wei Zheng; Stephen J Chanock; Douglas Easton; Brian M Wolpin; Rachael Z Stolzenberg-Solomon; Alison P Klein; Laufey T Amundadottir; Marc A Marti-Renom; Francisco X Real; Núria Malats Journal: Genome Med Date: 2021-02-01 Impact factor: 11.117
Authors: Guillermo Urrutia; Thiago Milech de Assuncao; Angela J Mathison; Ann Salmonson; Romica Kerketta; Atefeh Zeighami; Timothy J Stodola; Volkan Adsay; Burcin Pehlivanoglu; Michael B Dwinell; Michael T Zimmermann; Juan L Iovanna; Raul Urrutia; Gwen Lomberk Journal: Front Cell Dev Biol Date: 2021-06-23