LukS-PV Induces Apoptosis via the SET8-H4K20me1-PIK3CB Axis in Human Acute Myeloid Leukemia Cells

Xu, Liang; Shi, Liping; Zhang, Shan Shan; Ding, Peng; Song, Kai Di; Qiang, Ping; Chang, Wen Jiao; Dai, Yuan; Mei, Yi De; Xiao, Ling

doi:10.3389/fonc.2021.718791

Cited by 4 publications

(2 citation statements)

References 46 publications

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“…6F, G, K, L). As a critical transcription factor in regulating apoptosis and DNA repair [26], FOXO1 is a regulator of SET8/H4K2me1 [27]. Our study revealed that the levels of FOXO1 decreased following cisplatin exposure.…”

Section: Unc0379 and Set8 Silencing Restore Phosphatase And Tensin Ho...mentioning

confidence: 54%

Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

Zhuang,

Yang,

Guan

et al. 2023

Preprint

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SET8 is a histone H4 lysine 20 methyltransferase (H4K20) that regulates transcriptional and posttranslational modifications and is related to tumorigenesis and other diseases. Its role in acute kidney injury (AKI) remains unexplored. In this study, we investigated the role and underlying mechanism of SET8 in a murine model of cisplatin-induced AKI and apoptosis of cultured murine proximal tubular epithelial cells. Following cisplatin treatment, SET8 and H4K20 mono-methylation (H4K20me1) were upregulated, coincident with reduced expression of Phosphatase and Tensin Homolog (PTEN) and increased phosphorylation of p53 both in vivo and in vitro. Administration of UNC0379, a specific inhibitor, or siRNA-mediated silencing of SET8 significantly inhibited apoptosis of TKPTs following cisplatin exposure. Similarly, UNC0379 administration in cisplatin-injected mice attenuated tubular injury, apoptosis, and improved renal function. This was concomitant with the repression of SET8, H4K20me1, and p53 phosphorylation while restoring PTEN levels. Further investigations indicated that inhibition of PTEN with Bpv or siRNA aggravated cisplatin-induced apoptosis without affecting the expression of SET8 and H4K20me1. In contrast, inhibition of p53 with Pifithrin-alpha or silencing of p53 reduced cisplatin-induced apoptosis, but these treatments did not affect the expression of SET8, H4K20me1, and PTEN. Overall, these findings suggest that inhibition of SET8 relieves apoptosis by upregulating PTEN, which in turn represses p53 phosphorylation. Additionally, inhibiting SET8 significantly suppressed the phosphorylation of the histone variant H2A and p21, two proteins associated with DNA damages in vitro and in vivo. Therefore, our results suggest that SET8 may serve as a novel therapeutic target for cisplatin-induced AKI.

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Section: Unc0379 and Set8 Silencing Restore Phosphatase And Tensin Ho...mentioning

confidence: 54%

Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

Zhuang,

Yang,

Guan

et al. 2023

Preprint

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show abstract

“…SET domain-containing protein 8 (SET8) is a lysine monomethyltransferase, also called SETD8, which specifically methylates H4 lysine 20 [24]. SET8/H4K20me1 participates in the regulation of many signaling pathways, including the induction of apoptosis in cancer cells [25], mediating endothelial cell inflammation [26] and cellular oxidation [27]. Chen et al [28] showed that SET8/ H4K20me1 regulates Keap1-Nrf2/ARE to inhibit ROS accumulation from oxidative damage in hyperglycemia-induced endothelial injury.…”

Section: Prefacementioning

confidence: 99%

Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury

Qian

Shen

et al. 2023

Mediators of Inflammation

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Background. Spinal cord injury (SCI) is a common injury of the central nervous system (CNS), and astrocytes are relatively abundant glial cells in the CNS that impairs the recovery of motor function after SCI. It was confirmed that the oxidative stress of mitochondria leads to the accumulation of reactive oxygen species (ROS) in cells, which plays a key role in the motor function of astrocytes. However, the mechanism by which oxidative stress affects astrocyte motility after SCI is still unexplained. Therefore, this study investigated the influence of SET8-regulated oxidative stress on astrocyte autophagy levels after SCI in rats and the potential mechanisms of action. Methods. We used real-time quantitative PCR, western blotting, and immunohistochemical staining to analyze SET8, Keap1, and Nrf2 expression at the cellular level and in SCI tissues. ChIP to detect H4K20me1 enrichment in the Keap1 promoter region under OE-SET8 (overexpression of SET8) conditions. Western blotting was used to assess the expression of signature proteins of astrocytes, proteins associated with autophagy, proteins associated with glial scar formation, reactive oxygen species (ROS) levels in cells using DHE staining, and astrocyte number, morphological alterations, and induction of glial scar formation processes using immunofluorescence. In addition, the survival rate of neurons after SCI in rats was examined by using NiSSl staining. Results. OE-SET8 upregulates the enrichment of H4K20me1 in Keap1, inhibits Keap1 expression, activates the Nrf2-ARE signaling pathway to suppress ROS accumulation, inhibits oxidative stress-induced autophagy and glial scar formation in astrocytes, and leads to reduced neuronal loss, which promoted the recovery and improvement of motor function after SCI in rats. Conclusion. Overexpression of SET8 alleviated oxidative stress by regulating Keap1/Nrf2/ARE, inhibited astrocyte autophagy levels, and reduced glial scar formation as well as neuronal loss, thereby promoting improved recovery of motor function after SCI. Thus, the SET8/H4K20me1 regulatory function may be a promising cellular therapeutic intervention point after SCI.

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LukS-PV inhibits the proliferation of hepatocellular carcinoma cells by maintaining FOXO3 stability via the PI3K/AKT signaling pathway

Nie

Shi

Song

et al. 2022

Cellular Signalling

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LukS-PV Induces Apoptosis via the SET8-H4K20me1-PIK3CB Axis in Human Acute Myeloid Leukemia Cells

Cited by 4 publications

References 46 publications

Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury

LukS-PV inhibits the proliferation of hepatocellular carcinoma cells by maintaining FOXO3 stability via the PI3K/AKT signaling pathway

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