SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer
SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer
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DOI：
10.1158/1541-7786.mcr-17-0410
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发表时间：
2018-09-01
影响因子：
5.2
通讯作者：
Giguere, Vincent
中科院分区：
文献类型：
--
作者：
Audet-Walsh, Etienne;Vernier, Mathieu;Giguere, Vincent
细胞代谢的重编程是前列腺癌的一个重要特征，包括脂质代谢的改变。最近，观察到mTOR的核部分对于前列腺癌细胞的雄激素介导的代谢重编程是必需的。在本文中，证明了雄激素受体（AR）和mTOR与固醇调节元件结合转录因子1（SREBF 1）的调节区结合以控制其表达，而这些信号传导途径的双重激活也促进SREBF 1切割并将其易位至细胞核。因此，在用合成雄激素R1881处理后，诱导SREBF 1募集至其靶基因的调控区，这是在抑制mTOR信号传导途径后消除的作用。反过来，SREBF 1活性的药理学和遗传学抑制会损害雄激素介导的关键脂肪生成基因脂肪酸合酶（FATCH）和硬脂酰辅酶A去饱和酶（SCD 1）的诱导。与这些观察结果一致，SREBF 1、FREB和SCD 1基因的表达在人前列腺癌肿瘤临床标本中显著相关。在功能上，SREBF 1活性的阻断降低了雄激素驱动的脂质积累。有趣的是，在SREBF 1抑制后观察到的甘油三酯积累减少被线粒体呼吸增加所抵消，表明前列腺癌细胞中柠檬酸盐代谢的潜在重新布线。总之，这些数据定义了AR/mTOR核轴，在前列腺癌的背景下，作为一种新的途径调节SREBF 1的活性和柠檬酸metabolish.Implications：发现AR/mTOR复合物促进SREBF 1的表达和活性增强了我们对前列腺癌细胞生长所需的代谢适应的理解，并提出了新的治疗方法，以靶向肿瘤代谢的脆弱性。(C)2018年AACR。
Reprogramming of cellular metabolism is an important feature of prostate cancer, including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of prostate cancer cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element-binding transcription factor 1 (SREBF1) to control its expression, whereas dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus. Consequently, SREBF1 recruitment to regulatory regions of its target genes is induced upon treatment with the synthetic androgen R1881, an effect abrogated upon inhibition of the mTOR signaling pathway. In turn, pharmacologic and genetic inhibition of SREBF1 activity impairs the androgen-mediated induction of the key lipogenic genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1). Consistent with these observations, the expression of the SREBF1, FASN, and SCD1 genes is significantly correlated in human prostate cancer tumor clinical specimens. Functionally, blockade of SREBF1 activity reduces the androgen-driven lipid accumulation. Interestingly, decreased triglyceride accumulation observed upon SREBF1 inhibition is paralleled by an increase in mitochondrial respiration, indicating a potential rewiring of citrate metabolism in prostate cancer cells. Altogether, these data define an AR/mTOR nuclear axis, in the context of prostate cancer, as a novel pathway regulating SREBF1 activity and citrate metabolism.Implications: The finding that an AR/mTOR complex promotes SREBF1 expression and activity enhances our understanding of the metabolic adaptation necessary for prostate cancer cell growth and suggests novel therapeutic approaches to target metabolic vulnerabilities in tumors. (C) 2018 AACR.