IGF2BP2/ISG15/c-Myc axis promotes the excessive proliferation of granulosa cells in polycystic ovary syndrome.

Abstract

Objective: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder. This study aimed to investigate the role of IGF2BP2 in the pathogenesis of PCOS.

Methods: Dehydroepiandrosterone (DHEA) was used to establish mouse PCOS model. Histological analysis was conducted using HE staining and immunohistochemistry. Gene expression was detected using RT-qPCR and Western blot. Mitochondrial respiration was detected using OCR assay. Glycolysis was detected using ECAR assay. Cell viability was detected using CCK-8 assay. Cell proliferation was detected using colony formation and EdU assays.

Results: IGF2BP2 expression was upregulated in PCOS. However, overexpressed IGF2BP2 promoted mitochondrial respiration and glycolysis as well as the proliferation of human ovarian granulosa cells (KGN). IGF2BP2 knockdown inhibited mitochondrial respiration, glycolysis, and proliferation of KGN, leading to improved endocrine and reproductive function in vivo. Mechanically, IGF2BP2-mediated m6A modification promoted the upregulation of ISG15. ISG15 drove the ISGylation and upregulation of c-Myc, which transcriptionally activated IGF2BP2. Additionally, overexpressed ISG15 reversed the effects of IGF2BP2 knockdown and promoted the proliferation of KGN.

Conclusion: In summary, IGF2BP2-mediated m6A modification and upregulation of ISG15 contributes to excessive proliferation of GCs via mediating ISGylation of c-Myc. Moreover, IGF2BP2/ISG15/c-Myc axis forms a positive feedback loop to promote the progression of PCOS. These findings may provide novel therapeutic strategies for PCOS treatment.