Expression patterns of
estrogen receptors [ERα, ERβ, and
G-protein associated ER (GPER)] in
melanoma and skin may suggest their differential roles in
carcinogenesis. Phytoestrogenic compound cyanidin-3-o-glucoside (C3G) has been shown to inhibit the growth and metastatic potential of
melanoma, although the underlying molecular mechanism remains unclear. The aim of this study was to clarify the mechanism of action of C3G in
melanoma in vitro and in vivo, as well as to characterize the functional expressions of ERs in
melanoma. In normal skin or
melanoma (n = 20/each), no ERα
protein was detectable, whereas expression of ERβ was high in skin but weak focal or negative in
melanoma; and finally high expression of GPER in all skin vs. 50%
melanoma tissues (10/20) was found. These results correspond with our analysis of the
melanoma survival rates (SRs) from Human
Protein Atlas and The
Cancer Genome Atlas GDC (362 patients), where low ERβ expression in
melanoma correlate with a poor relapse-free survival, and no correlations were observed between SRs and ERα or GPER expression in
melanoma. Furthermore, we demonstrated that C3G treatment arrested the cell cycle at the G2/M phase by targeting
cyclin B1 (CCNB1) and promoted apoptosis via ERβ in both mouse and human
melanoma cell lines, and inhibited
melanoma cell growth in vivo. Our study suggested that C3G elicits an agonistic effect toward ERβ signaling enhancement, which may serve as a potential novel therapeutic and preventive approach for
melanoma.