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MiR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.

ABSTRACT: Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H₂O₂)-treated GCs and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. miR-181a overexpression promoted GC apoptosis, whereas knockdown of endogenous miR-181a blocked H₂O₂-induced cell apoptosis. Moreover, we identified that Sirtuin 1 (SIRT1), a deacetylase that suppresses FoxO1 acetylation in GCs, was downregulated by miR-181a and reversed the promoting effects of H₂O₂ and miR-181a on FoxO1 acetylation and GC apoptosis. Importantly, decreased miR-181a expression in the in vivo ovarian oxidative stress model inhibited apoptosis by upregulating SIRT1 expression and FoxO1 deacetylation. Together, our results suggest that miR-181a mediates oxidative stress-induced FoxO1 acetylation and GC apoptosis by targeting SIRT1 both in vitro and in vivo.

SUBMITTER: Zhang M

PROVIDER: S-EPMC5680589 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.

Zhang Mei M Zhang Qun Q Hu Yali Y Xu Lu L Jiang Yue Y Zhang Chunxue C Ding Lijun L Jiang Ruiwei R Sun Jianxin J Sun Haixiang H Yan Guijun G

Cell death & disease 20171005 10

Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-treated GCs and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. miR-181a overex ...[more]

PMID: 28981116

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Project description:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.

Project description:A microarray analysis of an animal model with experimental sepsis induced by caecal ligation and puncture revealed that the level of microRNA?195 (miR?195) was upregulated. However, to the best of our knowledge, the role of miR?195 in sepsis remains unknown. The present study investigated the effect of miR?195 on apoptosis in sepsis and investigated the underlying mechanism. The level of miR?195 was measured in human intestinal epithelial cells following exposure to lipopolysaccharide (LPS). Cell viability and apoptosis were detected using Cell Counting kit?8 and flow cytometry assays. The expression levels of apoptosis?associated proteins were determined using western blot analysis. In addition, a dual?luciferase reporter assay was employed to verify the association between miR?195 and sirtuin 1 (SIRT1). Furthermore, the SIRT1 inhibitor EX527 was applied to further confirm the regulatory network of miR?195/SIRT1 in LPS?induced apoptosis. It was demonstrated that LPS significantly inhibited cell viability and promoted cell apoptosis in NCM460 cells in a dose?dependent manner. In addition, miR?195 was significantly upregulated following LPS treatment. The present results revealed that silencing miR?195 prevented apoptosis and alleviated cell injury in LPS?induced NCM460 cells. Further investigation demonstrated that miR?195 bound directly to and negatively regulated SIRT1. Inhibition of SIRT1 reversed the protective effects of miR?195?silencing on the apoptosis and viability of NCM460 cells. Furthermore, silencing miR?195 prevented endoplasmic reticulum (ER) stress?induced apoptosis via a downregulation of SIRT1 and its downstream effectors, including activating transcription factor 4, C/EBP homologous protein, glucose?regulated protein 78 and growth arrest and DNA?damage protein 34, as well as the phosphorylation of eukaryotic translation initiation factor 2A. In conclusion, the present study revealed a novel mechanism by which miR?195 regulates SIRT1?mediated downstream effectors in ER stress?induced apoptosis in sepsis.

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MiR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.

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miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.

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