Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells

Upal Basu-Roy, N. Sumru Bayin, Kirk Rattanakorn, Eugenia Han, Dimitris G. Placantonakis, Alka Mansukhani () and Claudio Basilico ()
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Upal Basu-Roy: New York University School of Medicine
N. Sumru Bayin: New York University School of Medicine
Kirk Rattanakorn: New York University School of Medicine
Eugenia Han: New York University School of Medicine
Dimitris G. Placantonakis: New York University School of Medicine
Alka Mansukhani: New York University School of Medicine
Claudio Basilico: New York University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.

Date: 2015
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DOI: 10.1038/ncomms7411

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