SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen-response element (ERE).
SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen-response element (ERE).
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雌激素通过一种新型的内含子雌激素反应元件（ERE）诱导乳腺癌中的SLC22A5/OCTN2表达。
DOI：
10.1007/s10549-011-1925-0
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发表时间：
2012-07
影响因子：
3.8
通讯作者：
Brown, Powel H.
中科院分区：
文献类型：
--
作者：
Wang, Chunyu;Uray, Ivan P.;Mazumdar, Abhijit;Mayer, Julie Ann;Brown, Powel H.
雌激素信号是在乳腺癌发病过程中起关键作用的重要信号通路。在之前的转录谱研究中，我们在乳腺癌中发现了一组新的雌激素诱导基因。其中一个基因是溶质载体家族22成员5 (SLC22A5)，它编码多特异性有机阳离子转运体（也称为OCTN2）。在本研究中，我们发现雌激素以雌激素受体（ER）依赖的方式强烈刺激SLC22A5的表达，并且SLC22A5的表达与乳腺癌细胞系和组织标本中的ER状态相关。虽然SLC22A5近端启动子对雌激素没有反应，但下游的内含子增强子赋予雌激素诱导作用。该内含子增强子包含一个新发现的雌激素反应元件（ERE） （GGTCA-CTG-TGACT）和其他转录因子结合位点，如半个ERE和一个核受体相关1 （NR4A2/Nurr1）位点。雌激素对荧光素酶报告基因的诱导依赖于内含子增强子内的ERE和NR4A2位点。针对ER或Nurr1的小干扰RNA抑制雌激素诱导SLC22A5的表达，染色质免疫沉淀试验证实ER和Nurr1都被募集到该增强子上。在功能实验中，敲低SLC22A5抑制左卡尼汀的摄入，导致脂滴积聚，抑制乳腺癌细胞的增殖。这些结果表明SLC22A5是一个雌激素依赖性基因，通过一个新发现的内含子ERE调控。由于SLC22A5是肉碱稳态、脂质代谢和细胞增殖的关键调节因子，因此SLC22A5可能在未来成为乳腺癌的潜在治疗靶点。
Estrogen signaling is a critical pathway that plays a key role in the pathogenesis of breast cancer. In a previous transcriptional profiling study, we identified a novel panel of estrogen-induced genes in breast cancer. One of these genes is solute carrier family 22 member 5 (SLC22A5), which encodes a polyspecific organic cation transporter (also called OCTN2). In this study, we found that estrogen stimulates SLC22A5 expression robustly in an estrogen receptor (ER)-dependent manner and that SLC22A5 expression is associated with ER status in breast cancer cell lines and tissue specimens. Although the SLC22A5 proximal promoter is not responsive to estrogen, a downstream intronic enhancer confers estrogen inducibility. This intronic enhancer contains a newly identified estrogen-responsive element (ERE) (GGTCA-CTG-TGACT) and other transcription factor binding sites, such as a half ERE and a nuclear receptor related 1 (NR4A2/Nurr1) site. Estrogen induction of the luciferase reporter was dependent upon both the ERE and the NR4A2 site within the intronic enhancer. Small interfering RNA against either ER or Nurr1 inhibited estrogen induction of SLC22A5 expression, and chromatin immunoprecipitation assays confirmed the recruitment of both ER and Nurr1 to this enhancer. In functional assays, knockdown of SLC22A5 inhibited L-carnitine intake, resulted in lipid droplet accumulation, and suppressed the proliferation of breast cancer cells. These results demonstrate that SLC22A5 is an estrogen-dependent gene regulated via a newly identified intronic ERE. Since SLC22A5 is a critical regulator of carnitine homeostasis, lipid metabolism, and cell proliferation, SLC22A5 may serve as a potential therapeutic target for breast cancer in the future.
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影响因子：
--
作者：
DeNardo, DG;Kim, HT;Brown, PH
通讯作者：
Brown, PH
影响因子：
4.5
作者：
Lin CY;Vega VB;Thomsen JS;Zhang T;Kong SL;Xie M;Chiu KP;Lipovich L;Barnett DH;Stossi F;Yeo A;George J;Kuznetsov VA;Lee YK;Charn TH;Palanisamy N;Miller LD;Cheung E;Katzenellenbogen BS;Ruan Y;Bourque G;Wei CL;Liu ET
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Liu ET
影响因子：
30.8
作者：
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通讯作者：
Brown, Myles
影响因子：
50.3
作者：
Chin, Koei;DeVries, Sandy;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
64.8
作者：
Bild, AH;Yao, G;Nevins, JR
通讯作者：
Nevins, JR