title: SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells.
abstract: SOX2 is an essential transcription factor for stem cells and plays a role in tumorigenesis, however its role in prostate cancer stem cells (PCSCs) remains unclear. We report here a significant upregulation of SOX2 at both mRNA and protein levels in DU145 PCSCs propagated as suspension spheres in vitro. The expression of SOX2 in DU145 PCSCs is positively regulated by epidermal growth factor receptor (EGFR) signaling. Activation of EGFR signaling, following the addition of epidermal growth factor (EGF) or ectopic expression of a constitutively-active EGFR mutant (EGFRvIII), increased SOX2 expression and the self-renewal of DU145 PCSCs. Conversely, a small molecule EGFR inhibitor (AG1478) blocked EGFR activation, reduced SOX2 expression and inhibited PCSC self-renewal activity, implicating SOX2 in mediating EGFR-dependent self-renewal of PCSCs. In line with this notion, ectopic SOX2 expression enhanced EGF-induced self-renewal of DU145 PCSCs, while SOX2 knockdown reduced PCSC self-renewal with EGF treatment no longer capable of enhancing their propagation. Furthermore, SOX2 knockdown reduced the capacity of DU145 PCSCs to grow under anchorage-independent conditions. Finally, DU145 PCSCs generated xenograft tumors more aggressively with elevated levels of SOX2 expression compared to xenograft tumors derived from non-PCSCs. Collectively, we provide evidence that SOX2 plays a critical role in EGFR-mediated self-renewal of DU145 PCSCs.
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada; The Hamilton Centre for Kidney Research (HCKR), St. Joseph's Hospital, Hamilton, Ontario, Canada.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Rybak
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D066246:ErbB Receptors
keywords: EGFR; Prostate cancer stem cell; SOX2; Self-renewal