Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
Hepatology. 2021 Oct;74(4):1932-1951. doi: 10.1002/hep.31864. Epub 2021 Jul 13.
HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC.
Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC.
This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.
肝癌（HCC）是全球癌症相关死亡的主要原因，其预后较差，治疗选择有限。虽然髓细胞瘤（MYC）癌基因在 HCC 中经常失调，但人们认为它是不可治疗的。因此，本研究旨在确定 MYC 的关键下游代谢网络，并开发针对 MYC 驱动的 HCC 的治疗方法。
通过给予二乙基亚硝胺，在小鼠中诱导具有肝特异性 Myc 缺失的肝癌和对照小鼠。基于液相色谱-质谱联用的代谢组学分析显示，尿中二甲基精氨酸，特别是对称二甲基精氨酸（SDMA），在 MYC 依赖性方式下在 HCC 小鼠模型中增加。对人类样本的分析表明，HCC 患者尿液中也存在类似的 SDMA 诱导。从机制上讲，编码蛋白质精氨酸 N-甲基转移酶 5（Prmt5）的 Prmt5 高度诱导 HCC，并被鉴定为直接的 MYC 靶基因。此外，PRMT5 抑制剂 GSK3326595 抑制了自发性发生 HCC 的人 MYC 过表达转基因小鼠肝脏肿瘤的生长。PRMT5 抑制通过上调肿瘤抑制基因 Cdkn1b/p27（编码细胞周期蛋白依赖性激酶抑制剂 1B）发挥抗增殖活性。此外，GSK3326595 诱导淋巴细胞浸润和主要组织相容性复合体 II 表达，这可能有助于增强抗肿瘤免疫反应。GSK3326595 与程序性细胞死亡蛋白 1（PD-1）免疫检查点治疗（ICT）联合使用可提高 HCC 的治疗效果。
本研究揭示了 PRMT5 是 MYC 的表观遗传执行者，导致下游基因的转录调节受到抑制，从而促进肝细胞癌的发生，通过 PRMT5 抑制协同抑制增殖和增强抗肿瘤免疫，为 MYC 驱动的 HCC 提供了一种基于机制的治疗策略，并最终为减轻“免疫冷”肿瘤对 ICT 的耐药性提供了机会。
