MALAT1 downregulation is associated with polycystic ovary syndrome via binding with MDM2 and repressing P53 degradation

Polycystic ovary syndrome (PCOS) is a metabolic disorder of the reproductive system that affects 6-20% women of reproductive age. Multiple coding and non-coding genes were found to be affected in patients with PCOS, including MALAT1, an 8.7 kb long non-coding RNA. MALAT1 has been found to interact with miRNAs in granulosa cells (GCs); however, its binding proteins in GCs are still unknown. In this study, MALAT1 binding proteins in primary GCs were recruited by RNA antisense purification (RAP) assay and identified by mass spectrometry. The interaction between MALAT1 and proteins was examined by the PAR-CLIP assay and immunofluorescence. Functional studies were performed using the human granulosa-like tumor cell line (KGN) and primary granulosa cells. We identified that MALAT1 interacted with MDM2 and PARP1 in the cell nucleus. MDM2 binds to the 3' segment of MALAT1, containing the ENE domain through the ring finger domain. Knockdown of MALAT1 in GCs increased p53 protein levels by repressing p53 ubiquitination and degradation. MALAT1 promoted the binding between P53 and MDM2, which further boosted P53 proteasome dependent degradation. Knockdown of MALAT1 in KGN cells and primary GCs increased apoptosis and reduced proliferation.