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YAP-TEAD signaling promotes Basal Cell Carcinoma development via c-JUN/AP1 axis [ChIP-seq]

ABSTRACT: The mammalian Hippo signaling pathway, through its effectors YAP and TAZ, coerces epithelial progenitor cell expansion for appropriate tissue development or regeneration upon damage. Its ability to drive rapid tissue growth explains why many oncogenic events frequently exploit this pathway to promote cancer phenotypes. Indeed, several tumor types including basal cell carcinoma (BCC) show genetic aberrations in the Hippo (or YAP/TAZ) regulators. Here, we uncover that while YAP is dispensable for homeostatic epidermal regeneration, it is required for BCC development. Our clonal analyses further demonstrate that few emerging Yap-null dysplasia have lower fitness and thus are diminished as they progress to invasive BCC. Mechanistically, YAP depletion in BCC tumors leads to effective impairment of the JNK-JUN signaling, a well-established tumor driving cascade. Importantly, in this context, YAP does not influence canonical Wnt or Hedgehog signaling. Overall, we reveal the Hippo signaling as an independent promoter of BCC pathogenesis and thereby a viable target for drug-resistant BCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE115222 | GEO | 2018/09/04

REPOSITORIES: GEO

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YAP-TEAD signaling promotes Basal Cell Carcinoma development via c-JUN/AP1 axis [RNA-seq]

Project description:The mammalian Hippo signaling pathway, through its effectors YAP and TAZ, coerces epithelial progenitor cell expansion for appropriate tissue development or regeneration upon damage. Its ability to drive rapid tissue growth explains why many oncogenic events frequently exploit this pathway to promote cancer phenotypes. Indeed, several tumor types including basal cell carcinoma (BCC) show genetic aberrations in the Hippo (or YAP/TAZ) regulators. Here, we uncover that while YAP is dispensable for homeostatic epidermal regeneration, it is required for BCC development. Our clonal analyses further demonstrate that few emerging Yap-null dysplasia have lower fitness and thus are diminished as they progress to invasive BCC. Mechanistically, YAP depletion in BCC tumors leads to effective impairment of the JNK-JUN signaling, a well-established tumor driving cascade. Importantly, in this context, YAP does not influence canonical Wnt or Hedgehog signaling. Overall, we reveal the Hippo signaling as an independent promoter of BCC pathogenesis and thereby a viable target for drug-resistant BCC.

2018-09-04 | GSE115147 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [Invitro]

Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.

2023-10-04 | GSE222960 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [SubQ]

2023-10-04 | GSE222962 | GEO

Muscle stems cell LC-MS - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.

2017-06-13 | PXD005751 | Pride

Transcriptional targets of Hippo signaling in mammalian cells

Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.

2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress

Role of YAP/TAZ-TEAD in human trophoblast

Project description:During placentation, placental cytotrophoblast cells differentiate into syncytiotrophoblast cells and extravillous trophoblast cells. In placenta, the expression of various genes is regulated by the Hippo pathway through the transcriptional coactivator YAP/TAZ-TEAD activity. To examine the effect of YAP/TAZ and/or TEAD on trophoblast differentiation, knockdown experiments were performed. Microarray analysis were performed to identify YAP/TAZ and/or TEAD target genes in human trophoblast.

2022-07-17 | GSE182900 | GEO

CRKL enhances YAP signaling through binding and JNK/JUN pathway activation in liver cancer

Project description:Hepatocellular carcinoma (HCC) presents a major health issue due to its rising incidence and limited therapeutic options. The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tu-morigenesis promoting tumor formation and progression. Although first inhibitors are in clinical trials, targeting the upstream activation of YAP/TAZ could prove equally beneficial. To identify regulators of YAP/TAZ activity, we carried out a proximity labelling approach (BioID) coupled to mass-spectrometry. We verified CRKL as a new YAP-exclusive interaction partner, which is overexpressed in HCC patients correlating with YAP expression and activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL dependent cell survival and loss of YAP binding induced through actin disruption. Moreover, we delineated an activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data thus illustrated that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This highlights the JNK/JUN pathway as a possible target to abrogate YAP expression in HCC patients.

2024-11-26 | PXD058235 | Pride

The effect of YAP/TAZ knockdown on the intestinal epithelium

Project description:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.

2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress

Targeting YAP/TAZ-TEAD as a precision therapy approach in head and neck squamous cell carcinoma

Project description:Dysregulation of the Hippo pathway and the consequent activation of its downstream targets, the transcriptional co-activators YAP and TAZ (YAP/TAZ), drives oncogenic transcriptional programs upon binding TEAD transcription factors in multiple human malignancies. The recent development of small molecule TEAD inhibitors (smTEADi) provides an opportunity to therapeutically target Hippo pathway dysregulation in cancer. In this regard, HPV-negative head and neck squamous cell carcinoma (HNSCC) harbor multiple genetic alterations that promote YAP/TAZ hyperactivation, raising the possibility that HNSCC cells might be dependent on YAP/TAZ-TEAD driven oncogenic transcriptional programs. To test this hypothesis, we examined the antitumor activity of the novel smTEADi, SW-682 and genetically encoded TEAD inhibitor peptide (pTEADi) in Cal33 HPV-negative HNSCC cell line-derived xenograft model. To elucidate the transcriptomic changes upon YAP/TAZ-TEAD inhibition, RNA extracted from xenograft tumors treated with SW-682 or pTEADi, as well as control, was subjected to RNA sequencing.

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Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.

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