Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating ovulation dysfunction

Abstract

Background Disordered folliculogenesis is a core characteristic of polycystic ovary syndrome (PCOS) and androgen receptors (ARs) are closely associated with hyperandrogenism and abnormalities in folliculogenesis in PCOS. However, whether the new AR binding partner phosphoglycerate kinase 1 (PGK1) in granulosa cells (GCs) plays a key role in the pathogenesis of PCOS remains unclear. Methods We identified the new AR binding partner PGK1 by co-IP (co-immunoprecipitation) in luteinized GCs, and reconfirmed by co-IP, co-localization and GST pull down assay, and checked PGK1 expression levels with qRT-PCR and western blotting. Pharmaceuticals rescue assays in mice, and metabolism assay, AR protein stability and RNA-seq of PGK1 targets in cells proved the function in PCOS. Findings PGK1 and AR are highly expressed in PCOS luteinized GCs and PCOS-like mouse ovarian tissues. PGK1 regulated glucose metabolism and deteriorated PCOS-like mouse metabolic disorder, and paclitaxel rescued the phenotype of PCOS-like mice and reduced ovarian PGK1 and AR protein levels. PGK1 inhibited AR ubiquitination levels and increased AR stability in an E3 ligase SKP2-dependent manner. Additionally, PGK1 promoted AR nuclear translocation, and RNA-seq data showed that critical ovulation-related genes were regulated by the PGK1-AR axis. Interpretation PGK1 regulated GCs metabolism and interacted with AR to regulate the expression of key ovulation genes, and also mediated cell proliferation and apoptosis, which resulted in the etiology of PCOS. This work highlights the pathogenic mechanism and represents a novel therapeutic target for PCOS. Funding National Key Research and Development Program of China; National Natural Science Foundation of China grant.

β-Sitosterol Ameliorates Endometrium Receptivity in PCOS-Like Mice: The Mediation of Gut Microbiota

“…PCOS is characterized by excessive androgen secretion, low ovulation rate, and polycystic ovary (3), and is often accompanied by obesity and insulin resistance (4). Nowadays, research on women with infertility and PCOS mainly focuses on the aspects of ovulation dysfunction, sex hormones, and insulin resistance (5)(6)(7). However, insulin resistance could lead to insufficient glucose supply of endometrial cells, interfering with their growth and activity, thereby affecting endometrium receptivity (8), indicating that PCOS was closely related to endometrium receptivity.…”

Investigation of the mechanisms and experimental verification of Cuscuta-Salvia in the treatment of polycystic ovary syndrome (PCOS) via network pharmacology

“…TP53 levels can decrease in PCOS patients [ 44 ], while the MAPK1 levels are higher, leading to insulin resistance [ 16 ]. PCOS mice have been rescued by regulating the JUN pathway [ 29 ]. EGF overexpression has been measured in PCOS [ 3 ].…”

N6-methyladenosine reader YTHDF3 contributes to the aerobic glycolysis of osteosarcoma through stabilizing PGK1 stability

“…4A). It is a proven fact that PGK1 acts as an essential element in the tumor aerobic glycolysis and functions as an oncogene (Fu and Yu, 2020, Liu et al,, 2020, Zhang et al,, 2020. Predictive analysis (http://www.cuilab.cn/sramp) inspired that there were potential m 6 A modi ed sites in the PGK1 genome (Fig.…”