Studying signal transduction pathways and epigenetic mechanisms that control human SOX genes expression: further insight into their roles in cell fate determination and differentiation

Principal Investigator: Dr Milena Stevanovic, IMGGE

SOX proteins have important roles in pluripotency maintenance, cell fate determination and differentiation during development. Recent data point to the roles of these regulatory factors in oncogenesis. Major goals of this project are to analyze signaling pathways and epigenetic mechanisms involved in the regulation of human SOX genes expression and to elucidate their roles in neurogenesis and oncogenesis.

We investigated transcriptional and epigenetic mechanisms (DNA methylation, histone modifications and ncRNA-mediated processes) involved in the regulation of SOX genes expression. We also analyzed the effects of Wnt, Sonic Hedgehog (SHH), p53 and RA signaling pathways on the expression of selected SOX genes. Finally, we have studied the effects of modulation of SOX genes expression using gain- and loss-of-function approaches. Proposed research will enable further insights into the roles of SOX genes in control of neurogenesis. It will also shed the light on their multiple functions in the promotion of malignant potential and point to some SOXs as potential tumor biomarkers and/or therapeutic targets. 

The role of selected SOX genes in the process of neural differentiation was analyzed using pluripotent NT2-D1 cells as an in vitro model system for retinoic acid induced differentiation. Their specific roles in the promotion/inhibition of malignant phenotype have been examined in various in vitro model systems of human malignancies (glioblastoma, cervical, breast  and testicular carcinoma) and cancer stem cells.

Cancer stem cells are minor population of cells within tumor tissue with capabilities of self-renewal and differentiation. Accumulating studies have suggested that these cells are responsible for development and expansion of cancerous tissues, resistance to conventional chemotherapy/radiation treatment as well as poor prognosis. Accordingly, one of our aims was to study the roles of SOX genes in maintaining pluripotency and tumorigenic potential of cancer stem cells as well as in their responses to chemoradiotherapy.

Another applicative part of this project will include investigations of new bioactive compounds of natural or synthetic origin with neuroprotective or anticancer potential.

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