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.

中文翻译：

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褪黑素通过抑制雌激素/泛素C / SDHB介导的琥珀酸盐蓄积，减轻子宫内膜癌的进展。

琥珀酸酯是三羧酸循环的重要中间体。最近发现的琥珀酸盐的作用表明它参与了免疫和癌症生物学。但是，其参与这些其他角色的确切基础机制尚待确定。在本研究中，在雌激素的负调节下子宫内膜癌细胞（UECC）中的琥珀酸脱氢酶（SDH）B降低。这种下降是由于遍在蛋白C（UBC）的表达水平降低的结果，这与过氧化物酶体增殖物激活的受体γ和特异性蛋白1的激活有关。SDHB的降低导致琥珀酸盐在UECC中的积累，因此，减少了富马酸的产量。琥珀酸酯通过激活血清/糖皮质激素调节激酶1来下调电压门控钾通道亚家族Q成员1（KCNQ1）的水平，并在体外和体内促进UECC的生长。褪黑素治疗限制了雌激素/ UBC / SDHB诱导的琥珀酸积累，并上调了KCNQ1的表达，并减少了琥珀酸介导的UECC的体内外生长。此外，褪黑激素受体1B的过表达增强了褪黑激素对琥珀酸介导的UECC生长的抑制作用。总之，本研究中的数据表明褪黑激素通过抑制雌激素/ UBC / SDHB诱导的琥珀酸酯积累来抑制UECC进展。本研究为UEC的潜在治疗策略和目标，特别是SDHB异常低水平的患者提供了科学依据。