Ring Finger Protein 6 Mediates Androgen-Induced Granulosa Cell Proliferation and Follicle Growth via Modulation of Androgen Receptor Signaling.

The destiny of the ovarian follicle (growth or atresia) is tightly regulated by the actions and interactions of endocrine, paracrine, and autocrine factors. Although androgens are known to be important in the regulation of folliculogenesis, whether they facilitate or suppress follicular growth has been controversial, and the mechanisms involved are not fully understood. Moreover, the role and regulation of androgen receptor (AR) in mediating androgen signaling during follicular development is not clear. Here, we report that the active androgen dihydrotestosterone upregulates the expression of AR and its E3 ligase ring finger protein 6 (RNF6), increasing site-specific AR polyubiquitination and AR transcriptional activity for soluble Kit ligand (sKit-L) expression in preantral follicle growth. RNF6 silencing suppressed dihydrotestosterone-induced AR ubiquitination (lysine residue 63) and proliferation and suppressed apoptosis in preantral granulosa cells, with these responses being overcome by the presence of exogenous sKit-L. Taken together, our findings support the notion that RNF6 plays an important role in androgen-induced, follicle-stage-dependent follicle growth and that it acts by facilitating AR-mediated granulosa cell sKit-L expression and proliferation. Our findings offer insights into the regulatory mechanism of androgen action in ovarian follicular growth.