Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1.
Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1.
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DOI：
10.1158/0008-5472.can-12-3128
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Ting AH
中科院分区：
文献类型：
--
作者：
Lee BH;Taylor MG;Robinet P;Smith JD;Schweitzer J;Sehayek E;Falzarano SM;Magi-Galluzzi C;Klein EA;Ting AH
最近的流行病学数据显示，低血清胆固醇水平以及他汀类药物的使用与发展为侵袭性或晚期前列腺癌的风险降低相关，这表明胆固醇在侵袭性前列腺癌发展中的作用。细胞内胆固醇作为从头雄激素合成的底物并通过调节AKT信号传导促进前列腺癌进展。通过进行下一代基于测序的DNA甲基化组分析，我们发现LNCaP前列腺癌细胞中主要细胞胆固醇外排转运蛋白ABCA 1的启动子存在显著的超甲基化。ABCA 1启动子的高甲基化使得启动子对反式激活无反应，并导致LNCaP中胆固醇水平升高。ABCA 1启动子高甲基化在中高度前列腺癌中富集，在良性前列腺中检测不到。值得注意的是，ABCA 1下调在所有检查的前列腺癌中是明显的，并且表达水平与Gleason分级呈负相关。我们的研究结果表明，癌症特异性ABCA1超甲基化和蛋白表达的丧失直接导致细胞内胆固醇水平升高，因此有助于肿瘤进展的环境。
Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By performing next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to trans-activation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate to high grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 down-regulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression.