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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224264 | GEO | 2024/10/01

REPOSITORIES: GEO

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

Project description:The Hippo pathway downstream effectors YAP and TAZ display oncogenic potential via their transcriptional co-activator function, mediated primarily by binding to TEAD transcription factors. Many studies have focused on identifying YAP/TAZ-TEAD target genes, but their role in the regulation of protein synthesis has remained largely unexplored. Here we show that YAP activation is sufficient to overcome the global translation restriction of 5TOP-containing mRNAs, which is induced by serum deprivation and dependent on the inactivation of mTORC1. We found that YAP/TAZ repressed the expression of DDIT4, a negative regulator of mTORC1 whose expression is otherwise upregulated by serum deprivation. Forced expression of DDIT4 was sufficient to suppress translation and transformative potential of serum-unresponsive uveal melanoma cells, which harbor G protein mutations. Our findings highlight crosstalk between Hippo-YAP/TAZ and mTORC1 pathways in the regulation of translation and offer a new perspective towards understanding YAP/TAZ-driven malignancies.

2024-10-01 | GSE224261 | GEO

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

2024-10-01 | GSE224260 | GEO

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

2024-10-01 | GSE224263 | GEO

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

| PRJNA930423 | ENA

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

| PRJNA930427 | ENA

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

| PRJNA930428 | ENA

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

| PRJNA930426 | ENA

The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation.

Project description:Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis. Adaptation of transformed cells to nutrient withdrawal is severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of eEF2K strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme. Finally, C. elegans strains deficient in efk-1, the eEF2K ortholog, were severely compromised in their response to nutrient depletion. Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. PAPERCLIP:

| S-EPMC4395874 | biostudies-literature

YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation.

Project description:The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND). Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD) family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy.

| S-EPMC4374846 | biostudies-literature

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1.

Project description:Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.

| S-EPMC7958225 | biostudies-literature

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