Sox2, together with Oct4, Nanog and c-Myc, are the most important transcriptional factors for cell reprogramming. We report that in tumors, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1, leading to exaggerated YAP function.
Sox2 is highly expressed in human and murine osteosarcomas (mOSs), and is greatly enriched in cells capable of forming spheres in suspension culture.
Firstly, we have generated two cell lines from spontaneous osteosarcomas that arose in a mouse model in which Rb and p53 are deleted in the osteogenic lineage.
Next, we performed the microarray hybridization, the result indicate a differentially expressed gene sets. Among those changed genes, cell cycle progression and mitosis-related genes were downregulated on Sox2 deletion, thus prompting us to study the regulation of these components of the Hippo pathway in osteosarcomas.
Finally, we show that the ability of Sox2 to regulate YAP and Nf2 is maintained in other tumors, such as glioblastoma, and in cells which normally do not express Sox2, such as NIH-3T3 ﬁbroblasts, suggesting a conserved mechanism of regulation among different cell lineages and pathologies.
To summary, disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumors.