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YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in new targetable vulnerabilities in NF2-deficient tumor cells

ABSTRACT: The NF2 gene, which encodes the Merlin protein, is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2). Recent large-scale genome sequencing studies have also identified NF2 as one of the most frequently mutated genes in VHL-wild-type kidney cancers. Even though a wide array of downstream signaling pathways has been described for Merlin/NF2, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate for the first time that silencing of YAP/TAZ is sufficient to induce regression of pre-established NF2 deficient kidney tumors. Mechanistically, we show that YAP/TAZ ablation severely diminishes glycolysis by downregulating the transcription of several glycolytic enzymes and growth factors and RTK-PI3K-AKT signaling, resulting in growth arrest. On the other hand, YAP/TAZ depletion significantly increases mitochondrial respiration and overproduction of mitochondrial ROS, resulting in redox imbalance and oxidative stress cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPACdependent activation of the RAF-MEK-ERK pathway to be a novel resistance mechanism that allows NF2 deficient tumor cells to survive YAP/TAZ inhibition in vitro and in vivo. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms strong correlations of a YAP/TAZ signature with the expression of glycolysis, oxidative phosphorylation and lysosomal genes, validating the clinical relevance of our findings.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125408 | GEO | 2019/05/04

REPOSITORIES: GEO

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Gene expression changes caused by YAP overexpression and Nf2 deletion in the developing mouse brain

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2013-06-19 | E-GEOD-48078 | biostudies-arrayexpress

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

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2015-02-15 | E-GEOD-64965 | biostudies-arrayexpress

Integrin signaling regulates YAP/TAZ to control skin homeostasis

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Merlin/NF2-loss Driven Tumorigenesis Linked to CRL4(DCAF1)-Mediated Inhibition of the Hippo Pathway Components Lats1 and 2

Project description:Studies in drosophila have suggested that Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at or near the plasma membrane. In contrast, studies of Merlin-deficient tumor cells have indicated that Merlin suppresses tumorigenesis by entering into the nucleus where it inhibits the E3 ubiquitin ligase CRL4DCAF1. We found that CRL4DCAF1 promotes YAP and TEAD-dependent transcription by ubiquitylating and thereby inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2 mutant mesotheliomas, schwannomas and meningiomas. We conclude that de-repressed CRL4DCAF1 controls the output of the Hippo pathway by inhibiting Lats1 and 2 in the nucleus.

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2021-04-14 | GSE157677 | GEO

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2019-04-25 | PXD012017 | Pride

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