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; Claudio Basilico

doi:10.1038/ncomms7411

Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells

Nat Commun. 2015 Apr 2:6:6411. doi: 10.1038/ncomms7411.

Authors

Upal Basu-Roy¹, N Sumru Bayin², Kirk Rattanakorn¹, Eugenia Han³, Dimitris G Placantonakis², Alka Mansukhani¹, Claudio Basilico¹

Affiliations

¹ Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
² Department of Neurosurgery, New York University School of Medicine, New York, New York 10016, USA.
³ 1] Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA [2] Department of Pediatrics, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.

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

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic*
Glioblastoma / genetics*
Glioblastoma / metabolism
Hippo Signaling Pathway
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Neoplastic Stem Cells / metabolism*
Neurofibromin 2 / genetics
Neurofibromin 2 / metabolism
Osteosarcoma / genetics*
Osteosarcoma / metabolism
Phosphoproteins / genetics
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
RNA, Messenger / metabolism*
Real-Time Polymerase Chain Reaction
SOXB1 Transcription Factors / genetics*
SOXB1 Transcription Factors / metabolism
Signal Transduction
Transcription Factors
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
Neurofibromin 2
Phosphoproteins
RNA, Messenger
SOX2 protein, human
SOXB1 Transcription Factors
Transcription Factors
WWC1 protein, human
YAP-Signaling Proteins
YAP1 protein, human
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding