The Myb-MuvB Complex Is Required for YAP-Dependent Transcription of Mitotic Genes

Pattschull, Grit; Walz, Susanne; Gründl, Marco; Schwab, Melissa; Rühl, Eva; Baluapuri, Apoorva; Cindric-Vranesic, Anita; Kneitz, Susanne; Wolf, Elmar; Ade, Carsten P.; Rosenwald, Andreas; Eyß, Björn von; Gaubatz, Stefan

doi:10.1016/j.celrep.2019.05.071

Cited by 49 publications

(76 citation statements)

References 55 publications

(81 reference statements)

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“…YAP1-dependent cell lines and tumors showed enrichment in hallmarks related to cell cycle, such as the E2F targets, G2M checkpoint, MYC targets, and DNA repair pathways ( Figure 6C ). This is consistent with previous reports that have demonstrated that the transcription factors E2F and MYC are critical downstream regulators of YAP/TEAD-mediated activation of cell cycle genes ( Kapoor et al, 2014 ; Pattschull et al, 2019 ). While OSCC with high WWTR1 dependency signature score showed high expression of genes in several hallmarks related to immunity, such as the interferon responses, inflammatory responses and the complement pathway.…”

Section: Resultssupporting

confidence: 94%

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Chai

Yee

Price

et al. 2020

eLife

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New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favourable response towards immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1.

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Section: Resultssupporting

confidence: 94%

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Chai

Yee

Price

et al. 2020

eLife

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“…Gene ontology analysis revealed that the MYC/β-catenin signature enriched-among othersfor Yap/Taz transcriptional targets (Supporting Table S3). Moreover, 59 of 125 genes (~45%) in our MYC/β-catenin signature (as opposed to ~14% of all active genes) scored as direct Yap targets by chromatin immunoprecipitation (28,29) (Biagioni et al, manuscript in preparation; Supporting Table S3). Finally, gene set enrichment analysis revealed that several Yap/Taz signatures were also enriched in the transcriptional profiles of either MYC/β-cat Ex3 or MYC-overexpressing livers (Supporting Fig.…”

Section: Concomitant Activation Of Myc and β-Catenin Induces A Pro-prmentioning

confidence: 99%

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

et al. 2020

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BaCKgRoUND aND aIMS: Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. appRoaCH aND ReSUltS: We generated a mouse model allowing conditional activation of MYC and WNT/ β-catenin signaling (through either β-catenin activation or loss of APC-adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

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“…Given that Crim1 is characterized as a YAP1 target gene in a number of tumor cell lines 37 , 52 – 54 and is a critical regulator for lens development and lens epithelial integrity, 43 , 45 , 55 we examined Crim1 expression in the LEC of one-month-old Yap1 +/ − mice. The level of Crim1 mRNA in Yap1 +/ − LEC was reduced by 33% compared with WT LEC ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A number of genes have been identified as YAP1 targets, including Crim1. 37 – 41 CRIM1 is a type I transmembrane protein and has been studied in relation to cancer cell migration and invasion. 42 It is important for the maintenance of LEC polarity, proliferation, and adhesion interactions during lens development that most likely involves integrin signaling.…”

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confidence: 99%

Heterozygous Loss of Yap1 in Mice Causes Progressive Cataracts

Zhang

Kasetti

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose Yap1 encodes an evolutionarily conserved transcriptional coactivator and functions as a down-stream effector of the Hippo signaling pathway that controls tissue size and cell growth. Yap1 contributes to lens epithelial development. However, the effect of Yap1 haplodeficiency on the lens epithelium and its role in the development of cataracts has not been reported. The aim of the current study is to investigate Yap1 function and its regulatory mechanisms in lens epithelial cells (LECs). Methods Lens phenotypes were investigated in Yap1 heterozygous mutant mice by visual observation and histological and biochemical methods. Primary LEC cultures were used to study regulatory molecular mechanism. Results The heterozygous inactivation of Yap1 in mice caused cataracts during adulthood with defective LEC phenotypes. Despite a normal early development of the eye including the lens, the majority of Yap1 heterozygotes developed cataracts in the first six months of age. Cataract was preceded by multiple morphological defects in the lens epithelium, including decreased cell density and abnormal cell junctions. The low LEC density was coincident with reduced LEC proliferation. In addition, expression of the Yap1 target gene Crim1 was reduced in the Yap1 +/ − LEC, and overexpression of Crim1 restored Yap1 +/ − LEC cell proliferation in vitro. Conclusions Homozygosity of the Yap1 gene was critical for adequate Crim1 expression needed to maintain the constant proliferation of LEC and to maintain a normal - sized lens. Yap1 haplodeficiency leads to cataracts.

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The Myb-MuvB Complex Is Required for YAP-Dependent Transcription of Mitotic Genes

Cited by 49 publications

References 55 publications

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

Heterozygous Loss of Yap1 in Mice Causes Progressive Cataracts

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