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

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

Cancer research (2014-06-08)
Shumei Song, Jaffer A Ajani, Soichiro Honjo, Dipen M Maru, Qiongrong Chen, Ailing W Scott, Todd R Heallen, Lianchun Xiao, Wayne L Hofstetter, Brian Weston, Jeffrey H Lee, Roopma Wadhwa, Kazuki Sudo, John R Stroehlein, James F Martin, Mien-Chie Hung, Randy L Johnson
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.

MATERIALS
Product Number
Brand
Product Description

USP
Doxycycline hyclate, United States Pharmacopeia (USP) Reference Standard
Supelco
Doxycycline hyclate, VETRANAL®, analytical standard
Supelco
Doxycycline hyclate, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Doxycycline hyclate
Doxycycline hyclate, European Pharmacopoeia (EP) Reference Standard