TY - JOUR
T1 - Stress-triggered YAP1/SOX2 activation transcriptionally reprograms head and neck squamous cell carcinoma for the acquisition of stemness
AU - Omori, Hirofumi
AU - Sato, Kuniaki
AU - Nakano, Takafumi
AU - Wakasaki, Takahiro
AU - Toh, Satoshi
AU - Taguchi, Kenichi
AU - Nakagawa, Takashi
AU - Masuda, Muneyuki
N1 - Funding Information:
We are grateful for the funding provided by the Japanese Society for the Promotion of Science (MEXT/JSPS KAKENHI Grant Number JP16K11255 to M.M., and JP16K11256 to T.W.).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Purpose: The clinical importance of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) is well recognized. However, a reliable method for the detection of functioning CSC has not yet been established. We hypothesized that YAP1, a transcriptional coactivator, and SOX2, a master transcription factor of SCC, may cooperatively induce stemness through transcriptional reprogramming. Methods: We immunohistochemically examined the expression of SOX2 and YAP1 in the CD44 variant 9 (CD44v9)-positive invasion front. A CSC-inducible module was identified through a combination of siRNAs and sphere formation assays. YAP1 and SOX2 interactions were analyzed in vitro. Results: The triple overexpression of SOX2, YAP1, and CD44v9 was significantly associated with poor prognosis. TCGA data revealed that the CSC-inducible module, which was related to EMT and angiogenesis, was significantly correlated with poor prognosis. The KLF7 expression, representatively chosen from the module, also correlated with poor prognosis and was essential for sphere formation and CSC propagation. Sphere stress-activated YAP1 enhanced SOX2 activity. Conclusions: The stress-triggered activation of YAP1/SOX2 transcriptionally reprograms HNSCC for the acquisition of stemness. Triple SOX2, YAP1, and CD44v9 immunostaining assays may be useful for the selection of high-risk patients with functioning CSCs, and YAP1 targeting may lead to the development of a CSC-targeting therapy.
AB - Purpose: The clinical importance of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) is well recognized. However, a reliable method for the detection of functioning CSC has not yet been established. We hypothesized that YAP1, a transcriptional coactivator, and SOX2, a master transcription factor of SCC, may cooperatively induce stemness through transcriptional reprogramming. Methods: We immunohistochemically examined the expression of SOX2 and YAP1 in the CD44 variant 9 (CD44v9)-positive invasion front. A CSC-inducible module was identified through a combination of siRNAs and sphere formation assays. YAP1 and SOX2 interactions were analyzed in vitro. Results: The triple overexpression of SOX2, YAP1, and CD44v9 was significantly associated with poor prognosis. TCGA data revealed that the CSC-inducible module, which was related to EMT and angiogenesis, was significantly correlated with poor prognosis. The KLF7 expression, representatively chosen from the module, also correlated with poor prognosis and was essential for sphere formation and CSC propagation. Sphere stress-activated YAP1 enhanced SOX2 activity. Conclusions: The stress-triggered activation of YAP1/SOX2 transcriptionally reprograms HNSCC for the acquisition of stemness. Triple SOX2, YAP1, and CD44v9 immunostaining assays may be useful for the selection of high-risk patients with functioning CSCs, and YAP1 targeting may lead to the development of a CSC-targeting therapy.
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U2 - 10.1007/s00432-019-02995-z
DO - 10.1007/s00432-019-02995-z
M3 - Article
C2 - 31485767
AN - SCOPUS:85071739507
SN - 0171-5216
VL - 145
SP - 2433
EP - 2444
JO - Journal of Cancer Research and Clinical Oncology
JF - Journal of Cancer Research and Clinical Oncology
IS - 10
ER -
