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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.

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.

SUBMITTER: Basu-Roy U

PROVIDER: S-EPMC4429898 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.

Basu-Roy Upal U Bayin N Sumru NS Rattanakorn Kirk K Han Eugenia E Placantonakis Dimitris G DG Mansukhani Alka A Basilico Claudio C

Nature communications 20150402

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 hig ...[more]

PMID: 25832504

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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.

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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.

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