Epigenetic reactivation of PEG3 by EZH2 inhibitors suppresses renal clear cell carcinoma progress

Qiu, Teng; Ding, Yuanyuan; Qin, Jingting; Ren, Dexu; Xie, Mengru; Qian, Qilan; Wang, Yasong; Li, Ma; Jing, Aixin; Yang, Jing; Ma, Shaojie; Wang, Xiujun; Wang, Weiling; Ji, Jing; Li, Guanchu

doi:10.1016/j.cellsig.2023.110662

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…Hypermethylation, considered an early event in renal cell carcinoma (RCC), correlates with tumor invasiveness [30]. Inhibiting EZH2 can reactivate PEG3, thereby inhibiting RCC progression [31]. Surgery is the primary treatment for RCC, and nephron-sparing surgery (NSS) is the preferred option to minimize peripheral lesions [30].…”

Section: Discussionmentioning

confidence: 99%

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Zou,

Chen,

Zhou

et al. 2024

Kidney Blood Press Res

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Introduction: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and mortality. Inhibition of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) by its inhibitor 3-DZNeP (3-Deazaneplanocin A) exerts renal benefits in acute renal ischemia-reperfusion injury (IRI). However, the underlying mechanisms is not completely known. This study aimed to elucidate the pathological mechanism of EZH2 in renal IRI by combination of multi-omics analysis and expression profiling in a public clinical cohort. Methods: In this study, C57BL/6J mice were used to establish acute kidney injury model, which were treated with 3-DZNeP for 24 hours. Kidney samples were collected for RNA-seq analysis, which was combined with publicly available EZH2-ChIP-seq data of mouse embryonic stem cell for a joint analysis to identify differentially expressed genes. Several selected differentially expressed genes were verified by quantitative PCR. Finally, single-nucleus sequencing data and expression profiling in public clinical datasets were used to confirm the negative correlation of the selected genes with EZH2 expression. Results: 3-DZNeP treatment significantly improved renal pathology and function in IRI mice. Through RNA-seq analysis combined with EZH2 ChIP-seq database, 162 differentially expressed genes were found, which might be involved in EZH2-mediated pathology in IRI kidneys. Four differential expressed genes (Scd1, Cidea, Ghr, and Kl) related to lipid metabolism or cell growth were selected based on GO and KEGG enrichment analysis, which were validated by quantitative PCR. Data from snRNA-seq revealed the negative correlation of these four genes with Ezh2 expression in different subpopulations of proximal tubular cells in IRI mice in different pattern. Finally, the negative correlation of these four genes with EZH2 expression was confirmed in patients with acute kidney injury in two clinical datasets. Conclusions: Our study indicates that Scd1, Cidea, Ghr, and Kl are downstream genes regulated by EZH2 in AKI. Upregulation of EZH2 in AKI inhibits the expression of these four genes in different population of proximal tubular cells to minimize normal physiological function, and promote acute or chronic cell injuries following acute kidney injury.

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Section: Discussionmentioning

confidence: 99%

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Zou,

Chen,

Zhou

et al. 2024

Kidney Blood Press Res

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“…It has been previously found, that the PEG3 expression is significantly reduced in renal clear cell carcinoma (ccRCC) compared to non-tumor renal tissue, and in vitro studies have shown that knockout of PEG3 causes acceleration of ccRCC proliferation. Findings suggest that PEG3 is indispensable for the regulation of ccRCC progression (Qiu et al, 2023). Another DEG associated with cancer revealed in BPA-treated tissues is Apolipoprotein A1 (APOA1).…”

Section: Discussionmentioning

confidence: 99%

A comprehensive transcriptomic analysis of the bisphenol A affected kidney in mice

Wiszpolska,

Lepiarczyk,

Paukszto

et al. 2023

Front. Mol. Biosci.

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Introduction: Bisphenol A (BPA) is a substance belonging to the endocrine-disrupting chemicals, globally used in the production of polycarbonate plastics. It has been found that BPA enhances carcinogenesis, triggers obesity and exerts a pathogenic effect in several disorders, such as type 2 diabetes, asthma, or increased blood pressure. Recent studies have revealed, that BPA has a harmful impact on the kidneys function, therefore, the current research aimed to explore the specific molecular changes triggered in these organs after oral BPA exposure in mice.Materials and Methods: The experiment was carried out on 12 (3-month-old) female mice. Six mice served as controls. The other 6 mice were treated with BPA in the drinking water at a dose of 50 mg/kg b. w. for 3 months. Then animals were euthanized, the kidneys were collected, and extracted RNA was used to perform RNA-seq.Results: Applied multistep bioinformatics revealed 433 differentially expressed genes (DEGs) in the BPA-treated kidneys (232 upregulated and 201 downregulated). Additionally, 95 differentially expressed long-noncoding RNAs (DELs) were revealed in BPA samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations indicated that BPA exposure resulted in profound changes in several essential processes, such as oxidative phosphorylation, mitochondrial and ribosome function, or chemical carcinogenesis.Conclusion: The obtained novel results suggest that BPA has a harmful impact on the fundamental processes of the kidney and significantly impairs its function by inducing mitochondrial dysfunction leading to oxidative stress and reactive oxygen species production.

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“…That is, these pregnancy-specific stressors (e.g., financial distress) can be mutually exclusive from exposure to ACEs, exacerbating the association between ACEs and variable DNA methylation in infants. We specifically selected the imprinted genes PEG10/SGCE [ 29 , 30 ], NNAT , [ 31 , 32 ] IGF2 , [ 33 , 34 ] H19 [ 35 ], PLAGL1/HYMA1 , [ 36 ] PEG3 , [ 37 ] DLK1/MEG3, and MEG3-IG [ 38 , 39 ] for several reasons: 1) Perturbations in DNA methylation at these loci, particularly before germ layer specification, are stably transmitted during DNA replication to all subsequent lineages in the body throughout the life course [ 33 ]; 2) Imprinted genes are critically important to proper development and growth, and are known to be environmentally vulnerable to shifts in methylation [ 33 ]. Their importance is demonstrated by the fact that major abnormalities in imprinting are incompatible with life, while moderate abnormalities in imprinting are associated with a number of disorders and diseases, including cancer [ 34 ]; 3) DNA methylation profiles of imprinted genes are well documented; they are largely invariant across tissues, making it easier to identify deviations [ 38 ]; and 4) The DMRs of the above-mentioned genes chosen include four paternally methylated and four maternally methylated DMRs that contribute to establishment and/or maintenance of the imprinting status of 10 imprinted genes [ 29–39 ].…”

Section: Introductionmentioning

confidence: 99%

Maternal adverse childhood experiences (ACEs) and offspring imprinted gene DMR methylation at birth

Vidal,

Sosnowski,

Marchesoni

et al. 2023

Epigenetics

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Adverse childhood experiences (ACEs) contribute to numerous negative health outcomes across the life course and across generations. Here, we extend prior work by examining the association of maternal ACEs, and their interaction with financial stress and discrimination, with methylation status within eight differentially methylated regions (DMRs) in imprinted domains in newborns. ACEs, financial stress during pregnancy, and experience of discrimination were self-reported among 232 pregnant women. DNA methylation was assessed at PEG10 / SGCE, NNAT, IGF2, H19, PLAGL1 , PEG3 , MEG3-IG , and DLK1/MEG3 regulatory sequences using pyrosequencing. Using multivariable linear regression models, we found evidence to suggest that financial stress was associated with hypermethylation of MEG3-IG in non-Hispanic White newborns; discrimination was associated with hypermethylation of IGF2 and NNAT in Hispanic newborns, and with hypomethylation of PEG3 in non-Hispanic Black newborns. We also found evidence that maternal ACEs interacted with discrimination to predict offspring PLAGL1 altered DMR methylation, in addition to interactions between maternal ACEs score and discrimination predicting H19 and SGCE/PEG10 altered methylation in non-Hispanic White newborns. However, these interactions were not statistically significant after multiple testing corrections. Findings from this study suggest that maternal ACEs, discrimination, and financial stress are associated with newborn aberrant methylation in imprinted gene regions.

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Epigenetic reactivation of PEG3 by EZH2 inhibitors suppresses renal clear cell carcinoma progress

Cited by 5 publications

References 30 publications

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

Multi-omics Integrated Analysis of the Protective Effect of EZH2 inhibition in Mice with Renal Ischemia-Reperfusion Injury

A comprehensive transcriptomic analysis of the bisphenol A affected kidney in mice

Maternal adverse childhood experiences (ACEs) and offspring imprinted gene DMR methylation at birth

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