title: Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties.
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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ssong@mdanderson.org.
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Honjo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qiongrong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ailing W
authors.initials: AW
authors.lastname: Scott
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Heallen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lianchun
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hofstetter
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Brian
authors.initials: B
authors.lastname: Weston
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roopma
authors.initials: R
authors.lastname: Wadhwa
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John R
authors.initials: JR
authors.lastname: Stroehlein
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human