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The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq]

ABSTRACT: Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221117 | GEO | 2023/07/13

REPOSITORIES: GEO

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The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq_mouse]

Project description:Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

2023-07-13 | GSE232273 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [bulk RNA-seq]

2023-07-13 | GSE221104 | GEO

A BDNF-TrkB autocrine loop enhances senescent cell viability [RNA-seq]

Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.

2022-09-20 | GSE190998 | GEO

Oxylipin biosynthesis reinforces cellular senescence through a RAS/p53 feedback loop and allows detection of senolysis

Project description:Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis

2021-02-20 | ST001708 | MetabolomicsWorkbench

MacroH2A1 ChIP-seq from H-RasV12 expressing senescent IMR90 human primary lung fibroblasts

Project description:Oncogene induced senescence (OIS) is a tumor suppressive mechanism typified by stable proliferative arrest, a persistent DNA damage response and the senescent-associated secretory phenotype (SASP). MacroH2A1, a tumor suppressive histone variant, is upregulated during OIS. Using ChIP-seq, we found that macroH2A1 undergoes dramatic relocalization during OIS. SASP genes are enriched in macroH2A1-containing chromatin and macroH2A1 is a critical component of the positive feedback loop that maintains SASP expression. Endoplasmic reticulum (ER) stress, a feature of OIS that requires macroH2A1, leads to ATM activation. ER stress triggers a negative feedback loop reducing SASP expression by causing the ATM-dependent removal of macroH2A1 from SASP genes. MacroH2A1 represents a critical control point in the regulation of SASP expression during OIS by We demonstrate that SASP gene expression is regulated by the combined actions of a positive feedback loop that requires macroH2A1 and a negative feedback loop where ER stress leads to ATM activation critical for the removal of macroH2A1 from SASP genes and consequently their repression.

2015-08-19 | GSE64601 | GEO

RNA seq of prostate gland from WT, PTEN pc -/- and PTEN pc-/-;P53 -/- mice

Project description:Acute Pten loss initiates prostate tumorigenesis characterized by cellular senescence response. Senescent cells secrete a variety of pro inflammatory factors in the tumor microenvironment, which can support the survival, outgrowth and migration of tumor cells. Here we examine cytokines and cytokines-related factors gene expression in Ptenpc-/- senescent and in Ptenpc-/-; Trp53pc-/- non senescent tumors. RNAseq analysis confirmed the presence of cytokines, which were specifically up- and down-regulated in Ptenpc-/- senescent tumors (“core-SASP”) we also found a number of upregulated secreted factors that were “senescence-unrelated” both present in both Ptenpc-/- and Ptenpc-/-; Trp53pc-/- tumors.

2020-10-09 | E-MTAB-9624 | biostudies-arrayexpress

Conserved transcriptomic signatures and protein markers in cellular senescence models

Project description:Cellular senescence is described as an irreversible cell cycle arrest induced in response to various stresses. Senescent cells are characterised by heterogeneous signalling alterations, complex secretory phenotype, known as senescence-associated secretory phenotype (SASP), and diverse transcriptomic profile. With the aim to investigate senescence heterogeneity and identify conserved transctiptomic alterations and universal senescence markers, we performed RNA-seq and multiplex proteomic analysis in proteasome inhibition-induced and stress-induced premature senescence models of HFL1 and BJ human fibroblasts. Our data revealed diverse transcriptomic signatures, but also, 231 common differentially expressed genes related to cell division and ECM remodelling, and enriched pathways that remained conserved among the different models with senescence onset. Moreover, we identified a subset of proteins and validated them in replicative senescent models. These proteins are involved in cell cycle arrest and promote a pro-inflammatory environment in premature and replicative senescence models. We suggest that the simultaneous analysis of p21, p-c-JUN, BCL-xL and survivin in cellular lysates, and IL-8, GM-CSF, GDF-15 and GROa in culture supernatants can provide a powerful tool for the identification and monitoring of senescent cells and can support the assessment of the efficacy of potential senotherapeutic approaches.

2023-07-17 | GSE235768 | GEO

The lncRNA MIR31HG regulates the senescence associated secretory phenotype

Project description:Oncogene-induced senescence provides a barrier against malignant transformation. Senescent cells secrete pro-inflammatory cytokines, chemokines and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Paradoxically, the SASP can also negatively impact the neighbouring tissues through inducing an inflammatory environment that promotes tumorigenesis and aged-related pathologies. We have previously shown that the lncRNA MIR31HG is overexpressed and located in the cytoplasm during BRAF-induced senescence. In young proliferating cells, nuclear MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes (PRC1/2). Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with the translation factor YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which acts as upstream regulator inducing the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its cellular localization and place the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.

2021-03-02 | PXD017475 | Pride

Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts

Project description:Histone deacetylases (HDACs) are known to be a class of enzymes that remove acetyl groups from lysine chains on histones or other proteins, and play a crucial role in epigenetic regulation and aging process. Previous studies have identified that HDAC4 is down-regulated in aged and UV-irradiated skin in vivo. Therefore, HDAC4 may be an important role in skin aging process. However, the role of HDAC4 in skin aging is rarely known. In this study, we conducted the integrative transcriptome analysis of overexpression and knockdown of HDAC4, and UV- or H2O2-induced senescence in human dermal fibroblast and identified candidate genes which are regulated by HDAC4. Among these genes, DNA damage-inducible transcript 4 (DDIT4) was significantly regulated by HDAC4. We demonstrated that DDIT4 expression was downregulated during senescence and HDAC4 overexpression prevented senescence-induced decrease of DDIT4. In addition, overexpression of DDIT4 reduced SASP and aged-related genes that could promote aging, suggesting that DDIT4 may prevent senescence. Collectively, our results have shown that HDAC4 may play an important role in preventing skin aging by inducing DDIT4 expression.

2021-12-31 | GSE181329 | GEO

Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence

Project description:Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments (CCFs) in senescent cells. The activation of cGAS, in turn triggers the production of SASP factors via Stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence upon irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

2017-06-20 | GSE100102 | GEO

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