SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer

Edelman, H.E., McClymont, S.A., Tucker, T.R., Pineda, S., Beer, R.L., McCallion, A.S., Parsons, M.J.
Human molecular genetics   30(6): 485-499 (Journal)
Registered Authors
Beer, Rebecca, McCallion, Andy, Parsons, Michael
MeSH Terms
  • Animals
  • Biomarkers, Tumor/genetics
  • Biomarkers, Tumor/metabolism*
  • Carcinoma, Pancreatic Ductal/genetics
  • Carcinoma, Pancreatic Ductal/metabolism
  • Carcinoma, Pancreatic Ductal/pathology*
  • Cell Movement
  • Cell Proliferation
  • Cilia/genetics*
  • Cilia/metabolism
  • Epithelial Cell Adhesion Molecule/genetics
  • Epithelial Cell Adhesion Molecule/metabolism*
  • Humans
  • Pancreatic Neoplasms/genetics
  • Pancreatic Neoplasms/metabolism
  • Pancreatic Neoplasms/pathology*
  • SOX9 Transcription Factor/genetics
  • SOX9 Transcription Factor/metabolism*
  • Signal Transduction
  • Zebrafish
33693707 Full text @ Hum. Mol. Genet.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with high mortality. The cellular origins of PDAC are largely unknown, however, ductal cells, especially centroacinar cells (CACs), have several characteristics in common with PDAC, such as expression of SOX9 and components of the Notch-signaling pathway. Mutations in KRAS and alterations to Notch signaling are common in PDAC; and, both these pathways regulate the transcription factor SOX9. To identify genes regulated by SOX9, we performed siRNA knockdown of SOX9 followed by RNA-seq in PANC-1 cells, a human PDAC cell line. We report 93 differentially expressed (DE) genes, with convergence on alterations to Notch-signaling pathways and ciliogenesis. These results point to SOX9 and Notch activity being in a positive feedback loop; and, SOX9 regulating cilia production in PDAC. We additionally performed ChIP-seq in PANC-1 cells to identify direct targets of SOX9 binding and integrated these results with our DE gene list. Nine of the top ten downregulated genes have evidence of direct SOX9 binding at their promoter regions. One of these targets was the cancer stem cell marker EpCAM. Using whole-mount in situ hybridization to detect epcam transcript in zebrafish larvae, we demonstrated that epcam is a CAC marker and that Sox9 regulation of epcam expression is conserved in zebrafish. Additionally, we generated an epcam null mutant and observed pronounced defects in ciliogenesis during development. Our results provide a link between SOX9, EpCAM, and ciliary repression that can be exploited in improving our understanding of the cellular origins and mechanisms of PDAC.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes