Melatonin alleviates progression of uterine endometrial cancer by suppressing estrogen/ubiquitin C/SDHB-mediated succinate accumulation.

Abstract

Succinate is an important intermediate of the tricarboxylic acid cycle. Recently discovered roles of succinate demonstrate its involvement in immunity and cancer biology; however, the precise underlying mechanisms of its involvement in these additional roles remain to be determined. In the present study, succinate dehydrogenase (SDH) B was decreased in uterine endometrial cancer cells (UECC) under negative regulation of estrogen. This decrease was the result of lower expression levels of ubiquitin C (UBC), which was associated with the activation of peroxisome proliferator-activated receptor gamma and specificity protein 1. The decreased levels of SDHB resulted in the accumulation of succinate in UECC, and thus, a decrease in the production of fumaric acid. Succinate downregulated voltage-gated potassium channel subfamily Q member 1 (KCNQ1) levels by activating serum/glucocorticoid regulated kinase 1 and promoted the growth of UECC in vitro and in vivo. Treatment with melatonin restricted estrogen/UBC/SDHB-induced succinate accumulation and upregulated expression of KCNQ1 and reduced the succinate-mediated growth of UECC in vitro and in vivo. Furthermore, overexpression of melatonin receptor 1B amplified the inhibitory effects of melatonin on succinate-mediated UECC growth. Together, the data in the present study suggest that melatonin suppresses UECC progression by inhibiting estrogen/UBC/SDHB-induced succinate accumulation. The present study provides a scientific basis for potential therapeutic strategies and targets in UEC, particularly for patients with abnormally low levels of SDHB.