Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism.
Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.
Department of Surgery.
Filip
F
Bednar
Program in Cell and Molecular Biology, Medical Scientist Training Program.
Heather K
HK
Schofield
Program in Cell and Molecular Biology.
Meredith A
MA
Collins
Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA, Present address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Wei
W
Yan
Department of Surgery.
Yaqing
Y
Zhang
Medical Scientist Training Program.
Nikhil
N
Shyam
Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Jaime A
JA
Eberle
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Luciana L
LL
Almada
Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Kenneth P
KP
Olive
Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Nabeel
N
Bardeesy
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Martin E
ME
Fernandez-Zapico
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Daisuke
D
Nakada
Department of Surgery, Department of Molecular and Integrative Physiology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Diane M
DM
Simeone
Children's Research Institute, Department of Pediatrics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and.
Sean J
SJ
Morrison
Department of Surgery, Program in Cell and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA and marinapa@umich.edu.
Marina
M
Pasca di Magliano
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D063150:Polycomb Repressive Complex 1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)