Abstract 2440: Cross-tissue interactome analyses unravel novel oncogenic roles of SOX2

Abstract

Abstract First recognized for its significance in early embryogenesis, SOX2 (sex determining region Y box 2) more recently received major attention as a (i) transcriptional master regulator of stemness driving the re-programming of terminally differentiated somatic cells back into a pluripotent stem cell state and (ii) powerful oncogene of the cancer stem cell (CSC) compartment. We and others have shown that SOX2 expression relies on canonical PI3K/AKT signaling involving direct physical contact and phospho-modification by AKT. Interestingly, we observed that these interactions are highly tissue specific which prompted us to perform a systematic proteomic analysis of co-factors regulating SOX2 biology. The SOX2 interactome was analyzed in human breast carcinoma and glioblastoma cell lines by co-immunoprecipitation (co-IP) and HPLC/MS revealing >900 individual and >70 conserved proteinaceous co-factors, thus underscoring a hitherto underestimated scaffolding function of SOX2. As expected, a major proportion of binding partners cluster in functional categories implicated in DNA binding and/or nucleotide modification (e.g. helicases, transferases, and ligases). However, a near equal share of SOX2 associated factors fall into functional classes formally unrelated to transcription modulation such as cell adhesion, cytoskeletal organization, or metabolic adaptation. Using SOX2 knock-down and overexpression cells generated by lentiviral technology, we confirm co-regulation of SOX2 with selected binding partners. Moreover, we observe co-depletion of SOX2 and protein co-factors in cells of stalled AKT activity, and a molecular restoration of both upon proteasomal inhibition. We conclude that, besides its known significance in DNA activity control, the SOX2 protein engages in various interactions seemingly unrelated to transcription modulation. These newly discovered interactions are likely to synergize with canonical SOX2 functions (i.e. the induction and maintenance of stemness), but involve regulation at post-translational level and of extra-nuclear components. Our efforts thus add an exciting new facet to SOX2 biology and eventually, may open new therapeutic avenues for targeted anti-CSC therapy. Citation Format: Thorsten Schaefer, Silvia Candido, Hui Wang, Thomas Bock, Alexander Schmidt, Claudia Lengerke. Cross-tissue interactome analyses unravel novel oncogenic roles of SOX2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2017-2440