title: β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.
abstract: Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenbluh
authors.forename: Deepak
authors.initials: D
authors.lastname: Nijhawan
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cox
authors.forename: Xingnan
authors.initials: X
authors.lastname: Li
authors.forename: James T
authors.initials: JT
authors.lastname: Neal
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Schafer
authors.forename: Travis I
authors.initials: TI
authors.lastname: Zack
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Wang
authors.forename: Aviad
authors.initials: A
authors.lastname: Tsherniak
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schinzel
authors.forename: Diane D
authors.initials: DD
authors.lastname: Shao
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000196:embryology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000378:metabolism*; D051575:Proto-Oncogene Proteins c-yes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077022:Survivin; D020825:T-Box Domain Proteins / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D015027:Zebrafish / Q000196:embryology; D051020:bcl-X Protein / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D000077022:Survivin; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051020:bcl-X Protein; D051176:beta Catenin; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; D019061:src-Family Kinases