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.
| Original language | English |
|---|---|
| Pages (from-to) | 1457-1473 |
| Number of pages | 17 |
| Journal | Cell |
| Volume | 151 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 21 Dec 2012 |
| Externally published | Yes |
Cite this
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β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. / Rosenbluh, Joseph; Nijhawan, Deepak; Cox, Andrew G.; Li, Xingnan; Neal, James T.; Schafer, Eric J.; Zack, Travis I.; Wang, Xiaoxing; Tsherniak, Aviad; Schinzel, Anna C.; Shao, Diane D.; Schumacher, Steven E.; Weir, Barbara A.; Vazquez, Francisca; Cowley, Glenn S.; Root, David E.; Mesirov, Jill P.; Beroukhim, Rameen; Kuo, Calvin J.; Goessling, Wolfram; Hahn, William C.
In: Cell, Vol. 151, No. 7, 21.12.2012, p. 1457-1473.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis
AU - Rosenbluh, Joseph
AU - Nijhawan, Deepak
AU - Cox, Andrew G.
AU - Li, Xingnan
AU - Neal, James T.
AU - Schafer, Eric J.
AU - Zack, Travis I.
AU - Wang, Xiaoxing
AU - Tsherniak, Aviad
AU - Schinzel, Anna C.
AU - Shao, Diane D.
AU - Schumacher, Steven E.
AU - Weir, Barbara A.
AU - Vazquez, Francisca
AU - Cowley, Glenn S.
AU - Root, David E.
AU - Mesirov, Jill P.
AU - Beroukhim, Rameen
AU - Kuo, Calvin J.
AU - Goessling, Wolfram
AU - Hahn, William C.
PY - 2012/12/21
Y1 - 2012/12/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871576111&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.11.026
DO - 10.1016/j.cell.2012.11.026
M3 - Article
C2 - 23245941
AN - SCOPUS:84871576111
VL - 151
SP - 1457
EP - 1473
JO - Cell
JF - Cell
SN - 0092-8674
IS - 7
ER -