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Protein phosphatase 1 regulatory subunit 15 A promotes translation initiation and induces G2M phase arrest during cuproptosis in cancers.

ABSTRACT: Copper ions play a crucial role as cofactors for essential enzymes in cellular processes. However, when the intracellular concentration of copper ions exceeds the homeostatic threshold, they become toxic to cells. In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we investigated that PPP1R15A activated translation initiation by dephosphorylating eukaryotic translation initiation factor 2 subunit alpha at the S51 residue through protein phosphatase 1 and phosphorylating eukaryotic translation initiation factor 4E binding protein 1 at the T70 residue. In addition, PPP1R15A reduced H3K4 methylation by altering the phosphorylation of histone methyltransferases, which led to the silencing of MYC and G2M phase arrest.

SUBMITTER: Liu C

PROVIDER: S-EPMC10873343 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Protein phosphatase 1 regulatory subunit 15 A promotes translation initiation and induces G2M phase arrest during cuproptosis in cancers.

Liu Chunyu C Chen Liang L Cong Yukun Y Cheng Lulin L Shuai Yujun Y Lv Fang F Chen Kang K Song Yarong Y Xing Yifei Y

Cell death & disease 20240216 2

Copper ions play a crucial role as cofactors for essential enzymes in cellular processes. However, when the intracellular concentration of copper ions exceeds the homeostatic threshold, they become toxic to cells. In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we invest ...[more]

PMID: 38365764

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Project description:BackgroundGlucose metabolism plays a critical role in tumor progression. When glucose intake is insufficient and the tumor's growth rate exceeds its energy supply, tumor cells typically adapt and overcome the energy stress through compensatory mechanisms to maintain the survival of tumor cells, which may also be related to tumor recurrence or metastasis.MethodsDifferent concentrations of glucose were selected as the basis for the energy stress model of gastric cancer. Then CCK-8 and flow cytometry were used to detect its effects on cell proliferation, apoptosis, and cell cycle. Differentially expressed genes (DEGs) were screened by RNA sequencing and the regulated pathways were identified by gene set enrichment analysis. The regulatory relationship between the gene PPP1R15A and its transcription factor JUN was proved by ChIP-qPCR and dual-luciferase reporter assay. The gain and loss of function assays were conducted to examine the effects of PPP1R15A under energy stress in vivo and in vitro. Potential regulatory mechanisms of PPP1R15A were further analyzed through a combination of online databases, RNA sequencing, and metabolite sequencing. The regulation of PPP1R15A on cell autophagy under energy stress was detected by western blot, transmission electron microscope, mRFP-GFP-LC3 adenovirus and laser scanning confocal microscopy.ResultsPPP1R15A and the transcription factor JUN were significantly upregulated by glucose deprivation (0 mM vs. 25 mM), JUN combined with the promoter of PPP1R15A and activated its expression. Both PPP1R15A and JUN were highly expressed in gastric cancer tissues and were independent risk factors for prognosis in the gastric cancer cohort. Overexpression of PPP1R15A promoted cell proliferation, inhibited apoptosis, and was involved in cell cycle arrest. Further RNA and metabolite sequencing suggested that PPP1R15A was associated with cell autophagy. In vitro experiments confirmed that both glucose deprivation and overexpression of PPP1R15A promoted the biosynthesis of autolysosome and autophagosome, and activated the cleavage of LC3 complex in gastric cancer cells. Moreover, PPP1R15A knockdown inhibited cell autophagy induced by glucose deprivation.ConclusionsPPP1R15A sustained the survival of gastric cancer cells by regulating autophagy under energy stress to resist or adapt to harsh environments.

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Protein phosphatase 1 regulatory subunit 15 A promotes translation initiation and induces G2M phase arrest during cuproptosis in cancers.

Publications

Protein phosphatase 1 regulatory subunit 15 A promotes translation initiation and induces G2M phase arrest during cuproptosis in cancers.

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