Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin
Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin
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DOI：
10.1210/en.2005-0359
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发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Yoshimura, Y
中科院分区：
文献类型：
--
作者：
Uchida, H;Maruyama, T;Yoshimura, Y
组蛋白可逆乙酰化在基因转录过程中起着重要作用，它由组蛋白乙酰转移酶和去乙酰化酶控制。组蛋白去乙酰化酶抑制剂（HDA-CI），如阿司他丁A（TSA）和辛二酰苯胺异羟肟酸（SAHA），已被确定不仅作为抗癌药物，而且作为细胞分化诱导剂。在人类子宫内膜中，排卵后孕酮的产生指导雌激素引发的子宫内膜腺细胞分化，从而产生许多独特的生物活性物质，包括glycodelin，其对于月经周期分泌期的着床至关重要。在这项研究中，我们表明，TSA和SAHA，属于异羟肟酸组的HDACIs，可以诱导人子宫内膜腺癌细胞系，石川的表型（最初来源于子宫内膜的腺体成分），以时间和剂量依赖性的方式分化为与正常子宫内膜上皮非常相似，如通过形态学变化，糖原合成，和分泌期特异性蛋白质（包括glycodelin）的表达。TSA和SAHA在其最佳浓度下引起的增殖和分化调节作用与黄体酮和雌二醇联合治疗产生的作用相当或更有效。此外，glycodelin的基因沉默的小干扰RNA导致HDACI诱导的分化在石川细胞的封锁，表明子宫内膜上皮分化的glycodelin的需求。我们的研究结果共同表明，TSA和SAHA是子宫内膜腺细胞的有效分化诱导剂，提供了一个可能的治疗策略，通过靶向glycodelin调节子宫内膜功能的线索。
Histone reversible acetylation, which is controlled by histone acetyltransferases and deacetylases, plays a fundamental role in gene transcription. Histone deacetylase inhibitors (HDA-CIs), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have been characterized not only as anticancer drugs, but also as cytodifferentiation-inducing agents. In human endometrium, postovulatory production of progesterone directs estrogen-primed endometrial glandular cells to differentiate and thereby produce a number of unique bioactive substances, including glycodelin, that are critical for implantation at the secretory phase of the menstrual cycle. In this study, we show that TSA and SAHA, belonging to the hydroxamic acid group of HDACIs, can induce the phenotype of a human endometrial adenocarcinoma cell line, Ishikawa (originally derived from the glandular component of the endometrium), to differentiate to closely resemble normal endometrial epithelium in a time- and dose-dependent manner, as determined by morphological changes, synthesis of glycogen, and expression of secretory phase-specific proteins, including glycodelin. The proliferation- and differentiation-modulating effects elicited by TSA and SAHA at their optimal concentrations were comparable or more potent than those exerted by combined treatment with progesterone and estradiol. Furthermore, the gene silencing of glycodelin by small interference RNA resulted in the blockade of HDACI-induced differentiation in Ishikawa cells, suggesting the requirement for glycodelin for endometrial epithelial differentiation. Our results collectively indicate that TSA and SAHA are potent differentiation inducers for endometrial glandular cells, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.