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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic*
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Glioblastoma / genetics*
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Glioblastoma / metabolism
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Hippo Signaling Pathway
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Neoplastic Stem Cells / metabolism*
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Neurofibromin 2 / genetics
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Neurofibromin 2 / metabolism
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Osteosarcoma / genetics*
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Osteosarcoma / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / metabolism*
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Real-Time Polymerase Chain Reaction
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SOXB1 Transcription Factors / genetics*
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Transcription Factors
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Intracellular Signaling Peptides and Proteins
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Neurofibromin 2
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Phosphoproteins
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RNA, Messenger
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SOX2 protein, human
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SOXB1 Transcription Factors
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Transcription Factors
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WWC1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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Protein Serine-Threonine Kinases