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首页> 外文期刊>EBioMedicine >c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks
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c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

机译：c-Myc拮抗影响关键基因网络的前列腺癌中雄激素受体的转录活性。

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Highlights ? c-MYC and AR share one third of chromatin binding with enhancer-like features. ? c-MYC can repress the expression of a subset prostate cancer biomarkers, including PSA. ? c-MYC and AR antagonize the expression of, Glycine N-Methyltransferase (GNMT), responsible for sarcosine biosynthesis. Prostate cancer is a heterogeneous disease. The most frequently used biomarker in clinical setting, a well described androgen receptor target gene, PSA, still performs poorly in stratifying patients at real risk of death due to the disease. Despite this, therapeutic approaches focus on suppressing androgen receptor signaling. However, this is only one of the recurrent alterations found in patients. This study focuses on c-MYC and the effects of its deregulation in advanced prostate cancer. We find that there is an inverse relationship between established biomarkers expression, including PSA. This inverse relationship could be used in clinics to select beneficial therapeutic approaches for a subset of prostate cancer cases. Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.
机译：强调 ？ c-MYC和AR具有类似增强子特征的染色质结合的三分之一。 ？ c-MYC可以抑制包括PSA在内的前列腺癌生物标志物的表达。 ？ c-MYC和AR拮抗负责肌氨酸生物合成的甘氨酸N-甲基转移酶（GNMT）的表达。前列腺癌是一种异质性疾病。在临床环境中最常用的生物标记物，一个描述充分的雄激素受体靶基因PSA，在将因该疾病而导致实际死亡的危险的患者分层中仍然表现不佳。尽管如此，治疗方法仍集中在抑制雄激素受体信号传导上。但是，这只是在患者中发现的复发性改变之一。这项研究的重点是c-MYC及其解除调节在晚期前列腺癌中的作用。我们发现，已建立的生物标志物表达（包括PSA）之间存在反比关系。这种反比关系可以在临床中用于为一部分前列腺癌病例选择有益的治疗方法。前列腺癌（PCa）是男性中最常见的非皮肤癌。雄激素受体（AR）是一种配体激活的转录因子，是晚期疾病的主要药物靶标。然而，已显示多种其他转录因子和信号网络在患者中发生改变并影响AR活性。其中，致癌转录因子c-Myc已在多种恶性肿瘤中进行了广泛研究，在PCa中通常观察到c-Myc的蛋白质水平升高。但是，它对AR活动的影响仍然难以捉摸。在这项研究中，我们评估了c-Myc过表达对PCa细胞系模型中AR活性和转录输出的影响，并验证了c-MYC对患者样品中AR目标的拮抗作用。我们发现c-Myc过表达部分重编了AR染色质的占有率，并与改变的组蛋白标记分布有关，最显着的是H3K4me1和H3K27me3。我们发现c-Myc和AR共同占据了大量的结合位点，这些都表现出类似增强子的特征。有趣的是，c-Myc过表达拮抗了临床相关的AR靶基因。因此，举例来说，我们验证了患者样品中c-Myc与两个AR目标基因KLK3（别名PSA，前列腺特异抗原）和甘氨酸N-甲基转移酶（GNMT）之间的拮抗关系。我们的发现提供了公正的证据，证明MYC的过度表达会放松AR转录程序，这被认为是PCa的驱动力。

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