Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-1018.
Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160-1018.
J Biol Chem. 2020 May 15;295(20):7126-7137. doi: 10.1074/jbc.RA120.013401. Epub 2020 Apr 3.
Protein arginine methyltransferase 1 (PRMT1) is a key regulator of hepatic immune responses. Recently, we reported that PRMT1 regulates the tumor immune response in hepatocellular carcinoma (HCC). Here we found that PRMT1 expression in human HCC correlates with that of programmed cell death 1 ligand 1 (PD-L1), PD-L2, and other checkpoint genes. PRMT1 deletion in mice reduced PD-L1 and PD-L2 expression in tumors and reduced the efficiency of PD-1 antibody treatment in a diethylnitrosamine-induced HCC mouse model, suggesting that PRMT1 regulates the hepatic immune checkpoint. Mice had reduced PD-L1 and PD-L2 expression when PRMT1 was specifically deleted in tumor cells or macrophages, but PRMT1 deletion in dendritic cells did not alter PD-L1 and PD-L2 expression. rs975484 is a common polymorphism in the human gene promoter, and we found that it alters expression in blood monocytes and tumor-associated macrophages in human HCC. expression was higher in individuals with a GG genotype than in individuals with a CC genotype, and heterozygous carriers had intermediate expression. Luciferase reporter assays indicated that this differential expression is due to an extra C/EBPβ-binding site in the promoter of individuals carrying the minor G allele. The rs975484 genotype also correlated with PRMT1 target expression in HCC. Individuals with the GG genotype had significantly higher levels of the PRMT1 targets PD-L1, PD-L2, and VISTA than those with the CC genotype. We conclude that PRMT1 critically controls immune checkpoints in mice and humans and that the polymorphism rs975484 affects checkpoint gene expression in HCC.
蛋白质精氨酸甲基转移酶 1（PRMT1）是肝脏免疫反应的关键调节因子。最近，我们报道 PRMT1 调节肝细胞癌（HCC）中的肿瘤免疫反应。在这里，我们发现 PRMT1 在人类 HCC 中的表达与程序性细胞死亡 1 配体 1（PD-L1）、PD-L2 和其他检查点基因的表达相关。在小鼠中敲除 PRMT1 可降低肿瘤中 PD-L1 和 PD-L2 的表达，并降低 PD-1 抗体在二乙基亚硝胺诱导的 HCC 小鼠模型中的治疗效果，表明 PRMT1 调节肝脏免疫检查点。当 PRMT1 特异性在肿瘤细胞或巨噬细胞中缺失时，小鼠的 PD-L1 和 PD-L2 表达降低，但在树突状细胞中缺失 PRMT1 并不改变 PD-L1 和 PD-L2 的表达。rs975484 是人类 基因启动子中的常见多态性，我们发现它改变了人类 HCC 中血液单核细胞和肿瘤相关巨噬细胞中的 表达。与 CC 基因型个体相比，GG 基因型个体的 表达更高，杂合携带者的表达居中。荧光素酶报告基因分析表明，这种差异表达是由于携带次要 G 等位基因的个体 基因启动子中存在额外的 C/EBPβ 结合位点所致。rs975484 基因型也与 HCC 中的 PRMT1 靶基因表达相关。与 CC 基因型个体相比，GG 基因型个体的 PRMT1 靶基因 PD-L1、PD-L2 和 VISTA 的水平显著更高。我们得出结论，PRMT1 在小鼠和人类中严格控制免疫检查点，而 多态性 rs975484 影响 HCC 中的检查点基因表达。
