Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†
| Autor: | Ketan Shrestha, Avi Harlev, Tatiana Kisliouk, Sarah Manthe, Rina Meidan, Eliezer Girsh, Magdalena Szymanska |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
endocrine system diseases Cell Survival Resveratrol Antioxidants Cell Line Epigenesis Genetic 03 medical and health sciences Histone H3 chemistry.chemical_compound Hypoxia-Inducible Factor 1-Alpha 0302 clinical medicine Sirtuin 1 Luteal Cells Humans RNA Small Interfering Endothelin-2 030219 obstetrics & reproductive medicine Granulosa Cells biology Activator (genetics) food and beverages Cell Biology General Medicine Hypoxia-Inducible Factor 1 alpha Subunit Cell biology Oxygen enzymes and coenzymes (carbohydrates) 030104 developmental biology HIF1A Histone Reproductive Medicine chemistry Gene Expression Regulation biology.protein Female biological phenomena cell phenomena and immunity Chromatin immunoprecipitation hormones hormone substitutes and hormone antagonists |
| Zdroj: | Biology of reproduction. 104(2) |
| ISSN: | 1529-7268 |
| Popis: | Endothelin-2 (EDN2) expression in granulosa cells was previously shown to be highly dependent on the hypoxic mediator, hypoxia inducible factor 1 alpha (HIF1A). Here, we investigated whether sirtuin-1 (SIRT1), by deacetylating HIF1A and class III histones, modulates EDN2 in human granulosa-lutein cells (hGLCs). We found that HIF1A was markedly suppressed in the presence of resveratrol or a specific SIRT1 activator, SRT2104. In turn, hypoxia reduced SIRT1 levels, implying a mutually inhibitory interaction between hypoxia (HIF1A) and SIRT1. Consistent with reduced HIF1A transcriptional activity, SIRT1 activators, resveratrol, SRT2104, and metformin, each acting via different mechanisms, significantly inhibited EDN2. In support, knockdown of SIRT1 with siRNA markedly elevated EDN2, whereas adding SRT2104 to SIRT1-silenced cells abolished the stimulatory effect of siSIRT1 on EDN2 levels further demonstrating that EDN2 is negatively correlated with SIRT1. Next, we investigated whether SIRT1 can also mediate the repression of the EDN2 promoter via histone modification. Chromatin immunoprecipitation (ChIP) analysis revealed that SIRT1 is indeed bound to the EDN2 promoter and that elevated SIRT1 induced a 40% decrease in the acetylation of histone H3, suggesting that SIRT1 inhibits EDN2 promoter activity by inducing a repressive histone configuration. Importantly, SIRT1 activation, using SRT2104 or resveratrol, decreased the viable numbers of hGLC, and silencing SIRT1 enhanced hGLC viability. This effect may be mediated by reducing HIF1A and EDN2 levels, shown to promote cell survival. Taken together, these findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|