The Upregulation of HAS2-AS1 Relates to the Granulosa Cell Dysfunction by Repressing TGF-β Signaling and Upregulating HAS2

HAS2 antisense RNA 1 (HAS2-AS1) is a long noncoding RNA that has increased expression in mature granulosa cells (GCs) and contributes to cumulus expansion by regulating HAS2 expression. However, the roles of HAS2-AS1 during the pathological process of polycystic ovary syndrome (PCOS) are still unclear. This study investigated the roles of HAS2-AS1 in patients with PCOS. Here, a significant upregulation of HAS2-AS1 was found in the primary GCs from patients with PCOS, which was positively correlated with the level of the protein HAS2. The knockdown of HAS2 restored the upregulation of HAS2-AS1 in promoting migration but could not restore the effects of HAS2-AS1 overexpression in promoting proliferation and repressing apoptosis. Transforming growth factor β (TGF-β) upregulated HAS2-AS1 levels, while HAS2-AS1 functioned as a feedback inhibition factor repressing TGF-β signaling by inhibiting TGF-β receptor type 2 (TGFBR2) expression. HAS2-AS1 bonded with EZH2 and guided the polycomb complex 2 to the TGFBR2 promoter region. HAS2-AS1 overexpression induced H3K27 hypermethylation in the TGFBR2 promoter region and then repressed TGFBR2 transcription in KGN cells and primary GCs. In conclusion, we identified for the first time that HAS2-AS1 is upregulated in patients with PCOS and represses TGF-β signaling via inducing TGFBR2 promoter region hypermethylation, which allowed us to explore the pathological processes of PCOS.