胆固醇侧链裂解酶
芳香化酶
生物
滋养层
类固醇生成急性调节蛋白
下调和上调
类固醇生成因子1
胎盘
转录因子
发起人
内分泌学
内科学
细胞生物学
基因表达
细胞色素P450
基因
胎儿
生物化学
遗传学
新陈代谢
怀孕
癌症
乳腺癌
医学
核受体
作者
Hai‐Bin Zhu,Qianlei Ren,Zhe Yan,Shouying Xu,Jia-Hao Luo,Ximei Wu,Chao Tang
标识
DOI:10.1016/j.jgg.2021.07.014
摘要
Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy. The transcription factor gene heart and neural crest derivatives expressed 1 (Hand1) promotes differentiation of mouse trophoblast giant cells. However, the role of HAND1 in human trophoblasts remains unknown. Here, we report that HAND1 inhibits human trophoblastic progesterone (P4) and estradiol (E2) from cholesterol through downregulation of the expression of steroidogenic enzymes, including aromatase, P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1). Mechanically, although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter, it restrains transcription of P450scc by upregulation of the methylation status of P450scc gene promoter through its binding to ALKBH1, a demethylase. Unlike aromatase and P450scc, HAND1 decreases 3β-HSD1 mRNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein HuR. Finally, HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2. Thus, our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts, which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.
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