Bmi 1 is required for the initiation of pancreatic cancer through an Ink 4 a-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 longterm 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 KrasG12D-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.

[1]  M. Fernández-Zapico,et al.  The Transcription Factor GLI1 Modulates the Inflammatory Response during Pancreatic Tissue Remodeling* , 2014, The Journal of Biological Chemistry.

[2]  S. Morrison,et al.  Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain , 2014, eLife.

[3]  A. Krešo,et al.  Self-renewal as a therapeutic target in human colorectal cancer , 2013, Nature Medicine.

[4]  D. Simeone,et al.  Bmi1 Enhances Tumorigenicity and Cancer Stem Cell Function in Pancreatic Adenocarcinoma , 2013, PloS one.

[5]  M. Hebrok,et al.  Bmi1 is required for regeneration of the exocrine pancreas in mice. , 2012, Gastroenterology.

[6]  D. Reinberg,et al.  EZH2 couples pancreatic regeneration to neoplastic progression. , 2012, Genes & development.

[7]  C. Galbán,et al.  Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. , 2012, The Journal of clinical investigation.

[8]  Jason R. Gunn,et al.  Acute Pancreatitis Accelerates Initiation and Progression to Pancreatic Cancer in Mice Expressing Oncogenic Kras in the Nestin Cell Lineage , 2011, PloS one.

[9]  Scott E. Kern,et al.  Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis , 2011, Nature.

[10]  M. Barbacid,et al.  Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. , 2011, Cancer cell.

[11]  M. Esteller,et al.  Aberrant epigenetic landscape in cancer: how cellular identity goes awry. , 2010, Developmental cell.

[12]  D. Bar-Sagi,et al.  Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. , 2010, Cancer cell.

[13]  Jun Li,et al.  Bmi‐1 is related to proliferation, survival and poor prognosis in pancreatic cancer , 2010, Cancer science.

[14]  M. Hebrok,et al.  Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. , 2010, The Journal of clinical investigation.

[15]  F. Real,et al.  The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma , 2009, The Journal of pathology.

[16]  In Hye Lee,et al.  Bmi1 regulates mitochondrial function and the DNA damage response pathway , 2009, Nature.

[17]  M. Capecchi,et al.  Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis , 2009, Proceedings of the National Academy of Sciences.

[18]  A. Bhushan,et al.  Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. , 2009, Genes & development.

[19]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[20]  J. Lees,et al.  Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion , 2008, Proceedings of the National Academy of Sciences.

[21]  M. Capecchi,et al.  Bmi1 is expressed in vivo in intestinal stem cells , 2008, Nature Genetics.

[22]  O. van Tellingen,et al.  Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. , 2007, Cancer cell.

[23]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[24]  Daniel Chourrout,et al.  Genome Regulation by Polycomb and Trithorax Proteins , 2007, Cell.

[25]  T. Kawabe,et al.  Dysregulated Expression of Stem Cell Factor Bmi1 in Precancerous Lesions of the Gastrointestinal Tract , 2006, Clinical Cancer Research.

[26]  Anke Sparmann,et al.  Polycomb silencers control cell fate, development and cancer , 2006, Nature Reviews Cancer.

[27]  Ralph Weissleder,et al.  Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Y. Arsenijévic,et al.  Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. , 2005, Genes & development.

[29]  S. Morrison,et al.  Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. , 2005, Genes & development.

[30]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[31]  R. DePinho,et al.  Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. , 2003, Genes & development.

[32]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[33]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[34]  R. DePinho,et al.  The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus , 1999, Nature.

[35]  M. Sofroniew,et al.  Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. , 1994, Genes & development.

[36]  Anton Berns,et al.  Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging , 1991, Cell.

[37]  R. Hruban,et al.  Pancreatic cancer in mice and man: the Penn Workshop 2004. , 2006, Cancer research.

[38]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.