β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis

Joseph Rosenbluh, Deepak Nijhawan, Andrew G. Cox, Xingnan Li, James T. Neal, Eric J. Schafer, Travis I. Zack, Xiaoxing Wang, Aviad Tsherniak, Anna C. Schinzel, Diane D. Shao, Steven E. Schumacher, Barbara A. Weir, Francisca Vazquez, Glenn S. Cowley, David E. Root, Jill P. Mesirov, Rameen Beroukhim, Calvin J. Kuo, Wolfram GoesslingWilliam C. Hahn

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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 languageEnglish
Pages (from-to)1457-1473
Number of pages17
JournalCell
Volume151
Issue number7
DOIs
Publication statusPublished - 21 Dec 2012
Externally publishedYes

Cite this

Rosenbluh, J., Nijhawan, D., Cox, A. G., Li, X., Neal, J. T., Schafer, E. J., ... Hahn, W. C. (2012). β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell, 151(7), 1457-1473. https://doi.org/10.1016/j.cell.2012.11.026
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. / β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. In: Cell. 2012 ; Vol. 151, No. 7. pp. 1457-1473.
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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.",
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Rosenbluh, J, Nijhawan, D, Cox, AG, Li, X, Neal, JT, Schafer, EJ, Zack, TI, Wang, X, Tsherniak, A, Schinzel, AC, Shao, DD, Schumacher, SE, Weir, BA, Vazquez, F, Cowley, GS, Root, DE, Mesirov, JP, Beroukhim, R, Kuo, CJ, Goessling, W & Hahn, WC 2012, 'β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis', Cell, vol. 151, no. 7, pp. 1457-1473. https://doi.org/10.1016/j.cell.2012.11.026

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 journalArticleResearchpeer-review

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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.

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