Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
Medical Systems Biophysics and Bioengineering, Systems Pharmacology and Pharmacy Division, Leiden Academic Centre for Drug Research, Leiden university, 2333 CC Leiden, the Netherlands.
Mol Metab. 2022 Oct;64:101561. doi: 10.1016/j.molmet.2022.101561. Epub 2022 Aug 6.
Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program.
We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy.
MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells.
Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.
雄激素受体（AR）的异常活动是前列腺癌（PCa）和去势抵抗性前列腺癌（CRPC）发展和进展的主要原因。雄激素信号调节基因转录和脂质代谢，促进早期和晚期 PCa 中的肿瘤生长和治疗耐药性。尽管存在直接的 AR 信号抑制剂，但 AR 的表达和功能也可以通过表观遗传调控。具体而言，赖氨酸（K）特异性去甲基酶（KDMs），在 PCa 和 CRPC 表型中常过表达，调节 AR 转录程序。
我们使用多组学方法研究了 PCa 和 CRPC 中的 LSD1/UTX 抑制，两种 KDM。我们首先进行了线粒体应激测试，以评估用双 KDM 抑制剂 MC3324 治疗后的呼吸能力，然后进行了脂质组学、蛋白质组学和代谢分析。我们还使用声动力光谱法研究了细胞的机械特性。
MC3324 诱导了 H3K4me2 和 H3K27me3 的全局增加，并伴有雄激素反应性和非反应性 PCa 系统的显著生长停滞和凋亡。LSD1/UTX 抑制在转录和非转录水平下调了 AR，表现出癌症选择性，表明其在抵抗雄激素剥夺治疗方面具有潜在用途。由于 MC3324 改变了 PCa 和 CRPC 细胞系的蛋白质和脂质含量，因此会损害代谢活性。表观遗传抑制 LSD1/UTX 破坏了线粒体 ATP 的产生，并介导了脂质可塑性，影响了磷胆碱基，这是 PCa 和 CRPC 中细胞膜的一个重要结构元素，与癌细胞物理和机械特性的变化有关。
我们的数据表明，表观遗传学、激素信号、代谢物可用性、脂质含量和机械代谢过程之间存在一个网络。该网络可能能够识别出药理学干预的其他热点，并强调了 KDM 介导的表观遗传调节在 PCa 和 CRPC 中的关键作用。
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