Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription
Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription
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DOI：
10.1073/pnas.1221654110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Mercurio, Arthur M.
中科院分区：
文献类型：
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作者：
Mak, Paul;Chang, Cheng;Mercurio, Arthur M.
雌激素受体β（ER β）促进缺氧诱导因子1 α（HIF-1 α）的降解，这有助于这种激素受体维持上皮细胞和癌细胞分化的能力。虽然ER β的丢失和随后的HIF-1激活发生在前列腺癌中，具有深远的后果，但ER β促进HIF-1 α降解的机制尚不清楚。我们报道ER β调节脯氨酰羟化酶2（PHD 2）的配体（3 β-diol）依赖性转录，PHD 2也称为Egl nine同系物1（EGLN 1），2-酮戊二酸依赖性双加氧酶，其羟基化HIF-1 α并靶向其被von Hippel-Lindau肿瘤抑制因子识别并随后降解。ER β通过与PHD 2基因5' UTR中作为增强子的独特雌激素反应元件相互作用来促进PHD 2转录。PHD 2本身对于维持上皮分化至关重要。PHD 2表达的丧失或其功能的抑制导致具有上皮-间充质转化特征的去分化，并且去分化细胞中的外源性PHD 2表达可以恢复上皮表型。此外，在表达PHD 2的细胞中表达HIF-1 α不会诱导去分化，但在被PHD 2羟基化的脯氨酸残基中含有突变的HIF-1 α的表达诱导去分化。这些数据描述了调节HIF-1 α稳定性的独特机制，其涉及ER β介导的PHD 2转录调节，并且它们突出了PHD 2在维持上皮分化中的意想不到的作用。
Estrogen receptor beta (ER beta) promotes the degradation of hypoxia inducible factor 1 alpha (HIF-1 alpha), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ER beta and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ER beta promotes the degradation of HIF-1 alpha is unknown. We report that ER beta regulates the ligand (3 beta-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1 alpha and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ER beta promotes PHD2 transcription by interacting with a unique estrogen response element in the 5' UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1 alpha in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1 alpha containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1 alpha stability that involves ER beta-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.