Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, USA.
Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, Canada.
Oncogene. 2018 Feb 8;37(6):710-721. doi: 10.1038/onc.2017.385. Epub 2017 Oct 23.
Androgen receptor (AR) is a transcriptional activator that, in prostate cells, stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen-deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed. In this study, we examined the AR cistrome in a PCa cell line-derived CRPC model using integrated bioinformatical analyses. Significantly, we found that the AR cistrome is largely retained in the CRPC stage. In particular, AR-mediated lipid biosynthesis is highly conserved and reactivated during the progression to CRPC, and increased level of lipid synthesis is associated with poor prognosis. The restoration of lipid biosynthetic pathways is partially due to the increased expression of AR splice variants. Blocking lipid/cholesterol synthesis in AR variants-expressing CRPC cell line and xenograft models markedly reduces tumor growth through inhibition of mTOR pathway. Silencing the expression of a fatty acid elongase, ELOVL7, also leads to the regression of CRPC xenograft tumors. These results demonstrate the importance of reactivation of AR-regulated lipid biosynthetic pathways in driving CRPC progression, and suggest that ADTs may be therapeutically enhanced by blocking lipid biosynthetic pathways.
雄激素受体（AR）是一种转录激活因子，在前列腺细胞中，它刺激各种细胞功能所需的基因表达，包括代谢和增殖。AR 信号对于激素依赖性前列腺癌（PCa）的发展也是必不可少的，其活性可以被雄激素剥夺疗法（ADTs）阻断。尽管 PCa 患者最初对 ADTs 反应良好，但癌症不可避免地会复发并进展为致命的去势抵抗性前列腺癌（CRPC）。尽管在 CRPC 中尽管雄激素处于去势水平，但 AR 活性通常会恢复，但尚不清楚 AR 信号是否被显著重新编程。在这项研究中，我们使用综合生物信息学分析检查了源自 PCa 细胞系的 CRPC 模型中的 AR 顺式作用元件组。值得注意的是，我们发现 AR 顺式作用元件组在 CRPC 阶段基本保留。特别是，AR 介导的脂质生物合成在向 CRPC 进展过程中高度保守并重新激活，并且脂质合成水平的增加与预后不良相关。脂质生物合成途径的恢复部分归因于 AR 剪接变体表达的增加。在表达 AR 变体的 CRPC 细胞系和异种移植模型中阻断脂质/胆固醇合成会通过抑制 mTOR 途径显著减少肿瘤生长。沉默脂肪酸延长酶 ELOVL7 的表达也会导致 CRPC 异种移植肿瘤的消退。这些结果表明，在驱动 CRPC 进展中，AR 调节的脂质生物合成途径的重新激活非常重要，并表明 ADTs 可能通过阻断脂质生物合成途径得到治疗增强。
