Long Noncoding RNA HUPCOS Promotes Follicular Fluid Androgen Excess in PCOS Patients via Aromatase Inhibition

Abstract

Context Androgen excess is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. Objective To determine the role and mechanism of novel long noncoding RNA (lncRNA) highly up-regulated in PCOS (HUPCOS) in the androgen excess of PCOS patients. Design The lncRNA expression profile in granulosa cells derived from PCOS and non-PCOS women were analyzed by using microarray assay. Human granulosa cell line KGN was used for mechanism investigation. Setting This was a university-based study. Patients Thirty-eight PCOS and 38 control patients were recruited: 8 PCOS and 8 control samples used for microarray discovery, the remaining 30 PCOS cases and 30 controls for quantitative RT-PCR validation. Main Outcome Measures The aberrant expression lncRNA profile of PCOS patients was measured using microarray. The relationship of HUPCOS and follicular fluid testosterone was measured. Aromatase expression were analyzed after HUPCOS downregulation. HUPCOS interaction protein was confirmed by RNA pull-down. Results The significantly elevated lncRNA in PCOS granulosa cells was named HUPCOS, which was positively correlated with follicular fluid testosterone of PCOS patients. HUPCOS downregulation increased aromatase expression and promoted conversion of androgen to estrogen. RNA-binding protein with multiple splicing (RBPMS) was the most likely protein that combined with HUPCOS. Conclusions Our findings suggested that HUPCOS mediated androgen excess in follicular fluid of PCOS patients by suppressing aromatase expression via interaction with RBPMS.

Transcriptomic Data Analyses Reveal That Sow Fertility-Related lincRNA NORFA Is Essential for the Normal States and Functions of Granulosa Cells

“…Although thousands of lncRNAs in human or other organisms have been identified by highthroughput sequencing technology, only a few of them are well characterized (Liu et al, 2018;Stojic et al, 2020). Notably, only several lncRNAs including lncRNA-Neat1 (Nakagawa et al, 2014), lncRNA-HUPCOS (Che et al, 2020), and lncRNA-PVT1 (Liu et al, 2020) have been reported to be involved in the regulation of ovarian functions, such as steroid hormone secretion and corpus luteum formation. However, the role of lncRNAs in regulating follicular development, GC state, and functions remain unknown.…”

Long non-coding RNAs in ovarian granulosa cells

“…In addition, RNA-binding protein with multiple splicing RBPMS was identified as a direct binding protein of HUPCOS. This study showed that a novel lncRNA, HUPCOS, mediated androgen excess in the follicular fluid of PCOS patients by inhibiting aromatase expression via interaction with RBPMS [53].…”

Estrogen disorders: Interpreting the abnormal regulation of aromatase in granulosa cells (Review)

“…When androgen secretion is excessive, the high sensitivity of Gcs to FSH causes a large increase in AMH, and AMH in turn inhibits the effect of FSH on aromatase in follicles (106). Recently, che et al (107) found that the highly expressed lncRNA HUPcOS of granulosa cells in patients with PcOS can interact with RNA-binding protein with multiple splicing (RBPMS) and inhibit the expression of aromatase, thereby mediating the excess of androgen in the follicular fluid of PCOS patients Therefore, the decrease in the aromatase activity conversely helps maintain high androgen levels (102,107). In addition, CYP19A1 and A-Kinase anchor protein 95 (AKAP95) levels are significantly decreased in human luteinized Gcs of patients with PcOS.…”