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.

doi:10.1016/j.cell.2012.11.026

Cited by 759Hippo pathway signaling and YAP/TAZWnt/β-catenin signaling in development and cancerSignaling Pathways in Disease

β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

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Rosenbluh, Joseph, Nijhawan, Deepak, Cox, Andrew G., Li, Xingnan, Neal, James T., Schafer, Eric J., Zack, Travis I., Wang, Xiaoxing +13 more·2012·Cell

DOI 10.1016/j.cell.2012.11.026PMC PMC3530160

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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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YAP collaborates with other transcription regulators to alter gene expression, for example, in colon cancer cell lines YAP1, β-catenin and TBX5 transcriptional complex regulate target genes.
“Second, YAP collaborates with other transcription regulators to alter gene expression, for example, in colon cancer cell lines YAP1, β-catenin and TBX5 transcriptional complex regulate (TCFor TEAD-independent) target genes (72).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in Drosophila by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [72]
Overexpression of TEAD1, WWTR1, YAP1, or constitutively active YAP S6A in KCL cells caused resistance to MRTX-849.
“Conversely, overexpression of TEAD1 (Fig. 2D; Supplementary Fig. 2D), WWTR1 (Fig. 2E; Supplementary Fig. 2E), YAP1 (Fig. 2F; Supplementary Fig. 2F), or a constitutively active, nucleus-restricted form of YAP1 (38), YAP S6A (Fig. 2G; left panel; Supplementary Fig. 2G) in “KCL” cells (derived from KRAS G12C ;Stk11-/-mice; see Methods) caused drug resistance.”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [38]

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β-catenin–Driven Tumors Are Dependent on a YAP1 Transcriptional Complex
(2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-rw2012-235
l r x n
(2016)
β-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma
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Activation of β-Catenin and Yap1 in Human Hepatoblastoma and Induction of Hepatocarcinogenesis in Mice
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Authors: 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., Goessling, W., & Hahn, W. C.
Affiliations: Broad Institute (US)
Brigham and Women's Hospital (US)
Stanford Medicine (US)
Corresponding author: Hahn, William C.
ORCID: Rosenbluh, Joseph
Nijhawan, Deepak
Cox, Andrew G.
Neal, James T.
Zack, Travis I.
Wang, Xiaoxing
Tsherniak, Aviad
Shao, Diane D.
Schumacher, Steven E.
Cowley, Glenn S.
Root, David E.
Mesirov, Jill P.
Beroukhim, Rameen
Kuo, Calvin J.
Goessling, Wolfram
Hahn, William C.
Venue: Cell
Publisher: Elsevier BV
Published: 2012-12
Volume: 151
Issue: 7
Pages: 1457-1473
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2012.11.026
PMC: PMC3530160
OpenAlex: W2085039090
Cited by: 757
References: 71
Citations by year: 2026: 21 · 2025: 41 · 2024: 49 · 2023: 49 · 2022: 59 · 2021: 71 · 2020: 69 · 2019: 62 · 2018: 77 · 2017: 58 · 2016: 57 · 2015: 70 · 2014: 37 · 2013: 35 · 2012: 1
FWCI: 21.65
Type: journal article
Language: en
Update notices: erratum (2013-03-28)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (P50CA127003, RC2CA148268, U01CA151920, R01CA140545, R01CA109467, U54CA112962, U54CA143798)
National Institute of General Medical Sciences (T32GM007753, F32GM090437, R01GM074024)
National Institute of Diabetes and Digestive and Kidney Diseases (U24DK085532, R01DK085720, U01DK085527, R01DK090311, U01DK085532)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: β-catenin, YAP, TBX5, Wnt/β-catenin signaling, colon cancer, tumor cell survival, carcinogenesis, YES1, Bcl-xL, survivin, anti-apoptotic genes, transcriptional complex, small molecule inhibitors, cancer cell lines
MeSH terms: Survivin, YAP-Signaling Proteins, Animals, Cell Transformation, Neoplastic, Colon, Colonic Neoplasms, Humans, Mice, Nude, Phosphoproteins, Transcription Factors, Transcription, Genetic, Zebrafish, src-Family Kinases, T-Box Domain Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, bcl-X Protein, Inhibitor of Apoptosis Proteins, beta Catenin, Mice, Proto-Oncogene Proteins c-yes

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β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

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