D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

Xu, Xingxing; Shen, Xiya; Feng, Wenjin; Yang, Dongren; Jin, Lingting; Wang, Jiaojiao; Wang, Mianxian; Zhang, Ting; Xue, Feng; Zhang, Jingjing; Meng, Chaobo; Chen, Roumeng; Zheng, Xinru; Du, Leilei; Xuan, Lina; Wang, Ying; Xie, Tian; Huang, Zhihui

doi:10.18632/aging.103819

Cited by 25 publications

(20 citation statements)

References 63 publications

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“…Several previous studies have revealed that YAP‐CDK6 pathway inhibits cellular senescence (Q. Xie et al., 2013 ; X. Xu et al., 2020 ; Yang et al., 2021 ). Consistent with previous studies, in our studies, several lines of evidences suggest that YAP‐CDK6 signaling mediates D‐gal‐induced senescence of astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…4.9 | SAβ-gal staining SAβ-gal staining kit (G1580, Solarbio) was adopted to assess cellular senescence according to the protocol clearly provided by the manufacturer, as previously described (X. Xu et al, 2020).…”

Section: Induction Of Astrocyte Senescencementioning

confidence: 99%

“…Xie et al, 2013), human mesenchymal stem cells (Fu et al, 2019), human periodontal ligament stem cells (Jia et al, 2018), glioma cells (X. Xu et al, 2020), and hepatic stellate cells (Jin et al, 2017). However, it remains unclear whether YAP signaling regulates the senescence of astrocytes in aged brain and AD.…”

Section: Introductionmentioning

confidence: 99%

“…As a key effector of the Hippo signaling pathway, YAP has been shown to play an important roles in cell proliferation, differentiation and tissue regeneration (Bao et al., 2020 ; Rosado‐Olivieri et al., 2019 ; X. Shen et al., 2020 ; C. Xie et al., 2020 ). Recent evidence has shown that YAP signaling is closely related to individual aging and cellular senescence (Fu et al., 2019 ; Iwasa et al., 2013 ; Jia et al., 2018 ; Jin et al., 2017 ; Santinon et al., 2018 ; Q. Xie et al., 2013 ; X. Xu et al., 2020 ). YAP‐1 deficiency promotes health aging of Caenorhabditis elegans (Iwasa et al., 2013 ), and YAP inhibits the senescence of human fibroblast cells (Santinon et al., 2018 ; Q. Xie et al., 2013 ), human mesenchymal stem cells (Fu et al., 2019 ), human periodontal ligament stem cells (Jia et al., 2018 ), glioma cells (X. Xu et al., 2020 ), and hepatic stellate cells (Jin et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence has shown that YAP signaling is closely related to individual aging and cellular senescence (Fu et al., 2019 ; Iwasa et al., 2013 ; Jia et al., 2018 ; Jin et al., 2017 ; Santinon et al., 2018 ; Q. Xie et al., 2013 ; X. Xu et al., 2020 ). YAP‐1 deficiency promotes health aging of Caenorhabditis elegans (Iwasa et al., 2013 ), and YAP inhibits the senescence of human fibroblast cells (Santinon et al., 2018 ; Q. Xie et al., 2013 ), human mesenchymal stem cells (Fu et al., 2019 ), human periodontal ligament stem cells (Jia et al., 2018 ), glioma cells (X. Xu et al., 2020 ), and hepatic stellate cells (Jin et al., 2017 ). However, it remains unclear whether YAP signaling regulates the senescence of astrocytes in aged brain and AD.…”

Section: Introductionmentioning

confidence: 99%

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YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling

Shen

Wang

et al. 2021

Aging Cell

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Senescent astrocytes accumulate with aging and contribute to brain dysfunction and diseases such as Alzheimer's disease (AD), however, the mechanisms underlying the senescence of astrocytes during aging remain unclear. In the present study, we found that Yes‐associated Protein (YAP) was downregulated and inactivated in hippocampal astrocytes of aging mice and AD model mice, as well as in D‐galactose and paraquat‐induced senescent astrocytes, in a Hippo pathway‐dependent manner. Conditional knockout of YAP in astrocytes significantly promoted premature senescence of astrocytes, including reduction of cell proliferation, hypertrophic morphology, increase in senescence‐associated β‐galactosidase activity, and upregulation of several senescence‐associated genes such as p16, p53 and NF‐κB, and downregulation of Lamin B1. Further exploration of the underlying mechanism revealed that the expression of cyclin‐dependent kinase 6 (CDK6) was decreased in YAP knockout astrocytes in vivo and in vitro, and ectopic overexpression of CDK6 partially rescued YAP knockout‐induced senescence of astrocytes. Finally, activation of YAP signaling by XMU‐MP‐1 (an inhibitor of Hippo kinase MST1/2) partially rescued the senescence of astrocytes and improved the cognitive function of AD model mice and aging mice. Taken together, our studies identified unrecognized functions of YAP‐CDK6 pathway in preventing astrocytic senescence in vitro and in vivo, which may provide further insights and new targets for delaying brain aging and aging‐related neurodegenerative diseases such as AD.

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Section: Discussionmentioning

confidence: 99%

Section: Induction Of Astrocyte Senescencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling

Shen

Wang

et al. 2021

Aging Cell

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Yes‐associated protein regulates glutamate homeostasis through promoting the expression of excitatory amino acid transporter‐2 in astrocytes via β‐catenin signaling

Wang

et al. 2023

Glia

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The homeostasis of glutamate is mainly regulated by the excitatory amino acid transporters (EAATs), especially by EAAT2 in astrocytes. Excessive glutamate in the synaptic cleft caused by dysfunction or dysregulation of EAAT2 can lead to excitotoxicity, neuronal death and cognitive dysfunction. However, it remains unclear about the detailed regulation mechanism of expression and function of astrocytic EAAT2. In this study, first, we found increased neuronal death and impairment of cognitive function in YAPGFAP‐CKO mice (conditionally knock out Yes‐associated protein [YAP] in astrocytes), and identified EAAT2 as a downstream target of YAP through RNA sequencing. Second, the expression of EAAT2 was decreased in cultured YAP−/− astrocytes and the hippocampus of YAPGFAP‐CKO mice, and glutamate uptake was reduced in YAP−/− astrocytes, but increased in YAP‐upregulated astrocytes. Third, further investigation of the mechanism showed that the mRNA and protein levels of β‐catenin were decreased in YAP−/− astrocytes and increased in YAP‐upregulated astrocytes. Wnt3a activated YAP signaling and up‐regulated EAAT2 through β‐catenin. Furthermore, over‐expression or activation of β‐catenin partially restored the downregulation of EAAT2, the impairment of glutamate uptake, neuronal death and cognitive decline that caused by YAP deletion. Finally, activation of EAAT2 also rescued neuronal death and cognitive decline in YAPGFAP‐CKO mice. Taken together, our study identifies an unrecognized role of YAP signaling in the regulation of glutamate homeostasis through the β‐catenin/EAAT2 pathway in astrocytes, which may provide novel insights into the pathogenesis of brain diseases that closely related to the dysfunction or dysregulation of EAAT2, and promote the development of clinical strategy.

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