title: Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells.
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.
authors.affiliation: 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. lei.sun@nih.gov.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Mathews
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cabarcas
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Acong
authors.initials: A
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Young
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klarmann
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051996:Transcription Factor RelA
keywords: Cancer stem cells; Epigenetic regulation; Invasion; NF-κB signaling; Pancreatic cancer; SOX9