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1.
Cell Stem Cell ; 27(4): 590-604.e9, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32730753

ABSTRACT

Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to this state and thereby suppress tumor growth in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC. Finally, we demonstrate that genetic deletion of YAP and its paralog TAZ promotes the growth of these tumors. Collectively, our results establish the role of YAP as a tumor suppressor in the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectal malignancies.


Subject(s)
Cell Cycle Proteins , Colorectal Neoplasms , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Proliferation , Mice , Phosphoproteins/metabolism , Transcription Factors
2.
EMBO Mol Med ; 9(2): 181-197, 2017 02.
Article in English | MEDLINE | ID: mdl-28003334

ABSTRACT

Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins.


Subject(s)
Carcinogenesis , Colorectal Neoplasms/pathology , DNA Damage , Genes, Tumor Suppressor , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction , Ubiquitin-Protein Ligases/metabolism , Animals , Gene Deletion , Mice , Mutant Proteins/genetics , Mutant Proteins/metabolism , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases/genetics
3.
Mol Cell ; 60(2): 328-37, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26439301

ABSTRACT

The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP occupancy defines a subset of enhancers and superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Bile Duct Neoplasms/genetics , Cholangiocarcinoma/genetics , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Mediator Complex/genetics , Phosphoproteins/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Antineoplastic Agents/pharmacology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Carcinogenesis/drug effects , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line, Tumor , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/pathology , Chromatin/chemistry , Chromatin/metabolism , Cyclin-Dependent Kinase 9/genetics , Cyclin-Dependent Kinase 9/metabolism , DNA Polymerase II/genetics , DNA Polymerase II/metabolism , Enhancer Elements, Genetic , Flavonoids/pharmacology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mediator Complex/metabolism , Mice , Mice, Transgenic , Phosphoproteins/metabolism , Piperidines/pharmacology , Protein Binding , Signal Transduction , Trans-Activators , Transcription Factors , Transcription, Genetic , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Xenograft Model Antitumor Assays , YAP-Signaling Proteins
4.
Cell ; 157(6): 1324-1338, 2014 Jun 05.
Article in English | MEDLINE | ID: mdl-24906150

ABSTRACT

The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.


Subject(s)
Cell Dedifferentiation , Liver/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Cycle Proteins , Hepatocytes/metabolism , Hippo Signaling Pathway , Liver/cytology , Mice , Phosphoproteins/metabolism , Receptors, Notch/metabolism , Stem Cells/cytology , Stem Cells/metabolism , YAP-Signaling Proteins
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