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Cancer Res. 2014 Aug 1;74(15):4170-82. doi: 10.1158/0008-5472.CAN-13-3569. Epub 2014 Jun 6.

Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties.

Author information

  • 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ssong@mdanderson.org.
  • 2Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
  • 5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 6Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 8Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 9Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

Cancer stem cells (CSC) are purported to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of CSCs; however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional coactivator YAP1 is a major determinant of CSC properties in nontransformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSC properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenicity in vivo. The small-molecule inhibitor of YAP1, verteporfin, significantly blocks CSC properties in cells with high YAP1 and a high proportion of ALDH1(+). Our findings identify YAP1-driven SOX9 expression as a critical event in the acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.

©2014 American Association for Cancer Research.

PMID:
24906622
[PubMed - indexed for MEDLINE]
PMCID:
PMC4136429
[Available on 2015-08-01]
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