• Open Access

Epigenetic Regulation of SOX9 by the NF-κB Signaling Pathway in Pancreatic Cancer Stem Cells

Authors

  • Lei Sun,

    Corresponding author
    1. Cancer Stem Cell Section, Laboratory of Cancer Prevention, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
    • National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Building 560, Room 12-03, Frederick, Maryland 21702, USA===

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    • Telephone: (301) 846-6867; Fax: (301) 846-5951

  • Lesley A. Mathews,

    1. Cancer Stem Cell Section, Laboratory of Cancer Prevention, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
    2. Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
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  • Stephanie M. Cabarcas,

    1. Cancer Stem Cell Section, Laboratory of Cancer Prevention, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
    2. Department of Biology, Gannon University, Erie, Pennsylvania, USA
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  • Xiaohu Zhang,

    1. Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
    2. Basic Research Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
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  • Acong Yang,

    1. Laboratory of Protein Dynamics and Signaling, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
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  • Ying Zhang,

    1. Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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  • Matthew R. Young,

    1. Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
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  • Kimberly D. Klarmann,

    1. Basic Research Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
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  • Jonathan R. Keller,

    1. Basic Research Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
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  • William L. Farrar

    1. Cancer Stem Cell Section, Laboratory of Cancer Prevention, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
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  • Author contributions: L.S.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; L.A.M.: Conception and design and collection and assembly of data; S.M.C.: collection and assembly of data and manuscript editing; X.Z., A.Y., and Y.Z.: collection of data; M.R.Y.: mouse study design and data analysis and interpretation; K.D.K.: data analysis and interpretation and manuscript editing; J.R.K.: financial support and manuscript editing; W.L.F.: conception and design, financial support, and final approval of manuscript.

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related mortality in the world. Pancreatic cancer can be localized, locally advanced, or metastatic. The median 1- and 5-year survival rates are 25% and 6%, respectively. Epigenetic modifications such as DNA methylation play a significant role during both normal human development and cancer progression. To investigate epigenetic regulation of genes in the tumor-initiating population of pancreatic cancer cells, which are also termed cancer stem cells (CSCs), we conducted epigenetic arrays in PANC1 and HPAC pancreatic cancer cell lines and compared the global DNA methylation status of CpG promoters in invasive cells, demonstrated to be CSCs, to their noninvasive counterparts, or non-CSCs. Our results suggested that the NF-κB pathway is one of the most activated pathways in pancreatic CSCs. In agreement with this, we determined that upon treatment with NF-κB pathway inhibitors, the stem cell-like properties of cells are significantly disrupted. Moreover, SOX9, demethylated in CSCs, is shown to play a crucial role in the invasion process. Additionally, we found a potential NF-κB binding site located in the SOX9 promoter and determined that the NF-κB subunit p65 positively regulates SOX9 expression by binding to its promoter directly. This interaction can be efficiently blocked by NF-κB inhibitors. Thus, our work establishes a link between the classic NF-κB signaling transduction pathway and the invasiveness of pancreatic CSCs, which may result in the identification of novel signals and molecules that function at an epigenetic level, and could potentially be targeted for pharmaceutical investigations and clinical trials. STEM Cells 2013;31:1454–1466

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