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 Goessling; William C. Hahn

doi:10.1016/j.cell.2012.11.026

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

Research output: Contribution to journal › Article › Research › peer-review

433 Citations (Scopus)

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	https://doi.org/10.1016/j.cell.2012.11.026
Publication status	Published - 21 Dec 2012
Externally published	Yes

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10.1016/j.cell.2012.11.026

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Rosenbluh, J., Nijhawan, D., Cox, A. G., Li, X., Neal, J. T., Schafer, E. J., Zack, T. I., Wang, X., Tsherniak, A., Schinzel, A. C., Shao, D. D., Schumacher, S. E., Weir, B. A., Vazquez, F., Cowley, G. S., Root, D. E., Mesirov, J. P., Beroukhim, R., Kuo, C. 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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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.",

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

year = "2012",

month = dec,

day = "21",

doi = "10.1016/j.cell.2012.11.026",

language = "English",

volume = "151",

pages = "1457--1473",

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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 journal › Article › Research › peer-review

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AU - Shao, Diane D.

AU - Schumacher, Steven E.

AU - Weir, Barbara A.

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AU - Cowley, Glenn S.

AU - Root, David E.

AU - Mesirov, Jill P.

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AU - Hahn, William C.

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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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