Department of Pathology, School of Medicine, University of Patras, Patras, Greece.
Multidimensional Data Analysis and Knowledge Management Laboratory, Computer Engineering and Informatics Department, School of Engineering, University of Patras, Patras, Greece.
Histol Histopathol. 2023 Mar;38(3):287-302. doi: 10.14670/HH-18-513. Epub 2022 Sep 9.
Protein arginine methylation is an understudied epigenetic mechanism catalyzed by enzymes known as Protein Methyltransferases of Arginine (PRMTs), while the opposite reaction is performed by Jumonji domain- containing protein 6 (JMJD6). There is increasing evidence that PRMTs are deregulated in prostate cancer (PCa). In this study, the expression of two PRMT members, PRMT2 and PRMT7 as well as JMJD6, a demethylase, was analyzed in PCa. Initially, we retrieved data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) database to explore the differential expression of various PRMT family members in patients with PCa and then applied immunohistochemistry in a patient cohort across the spectrum of PCa, including non-neoplastic prostate tissue and lymph node metastatic foci. The results from the TCGA analysis revealed that PRMT7, PRMT6 and PRMT3 expression increased while PRMT2, PRMT9 and JMJD6 levels decreased in the tumor compared to non-neoplastic prostate. Results from the GEO datasets were similar, albeit not identical with the TCGA results, with PRMT7 and PRMT3 being upregulated and PRMT2 and JMJD6 being downregulated in the tumor compared to non-neoplastic tissue in some of them. In addition, PRMT7 levels decreased with stage and grade progression in the TCGA analysis. In the patient cohort, both PRMTs and JMJD6 were overexpressed in PCa compared to non-neoplastic tissue, and nuclear PRMT2 and JMJD6 were upregulated in lymph node metastasis, too. PRMT7 and JMJD6 expression were upregulated with the progression of stage and JMJD6 was also increased with the elevation of grade. After androgen ablation therapy, nuclear expression of PRMT7 and JMJD6 were elevated compared to untreated tumors. PRMT2, PRMT7 and JMD6 were also correlated with markers of EMT and cell cycle regulators. Finally, our findings indicate that PRMTs and JMJD6 are involved in prostate cancer progression and revealed a potential interplay of PRMTs with EMT mediators, underscoring the need for therapeutic targeting of arginine methylation in prostate cancer.
蛋白质精氨酸甲基化是一种研究较少的表观遗传机制，由精氨酸蛋白甲基转移酶（PRMTs）等酶催化，而相反的反应则由含 Jumonji 结构域蛋白 6（JMJD6）完成。越来越多的证据表明，PRMTs 在前列腺癌（PCa）中失调。在这项研究中，分析了两种 PRMT 成员 PRMT2 和 PRMT7 以及去甲基酶 JMJD6 在 PCa 中的表达。最初，我们从癌症基因组图谱（TCGA）项目和基因表达综合数据库（GEO）中检索数据，以探讨不同 PRMT 家族成员在 PCa 患者中的差异表达，然后在包括非肿瘤性前列腺组织和淋巴结转移性病灶的 PCa 患者队列中应用免疫组织化学。TCGA 分析的结果表明，与非肿瘤性前列腺相比，肿瘤中 PRMT7、PRMT6 和 PRMT3 的表达增加，而 PRMT2、PRMT9 和 JMJD6 的水平降低。GEO 数据集的结果相似，尽管与 TCGA 结果不完全相同，其中一些数据集显示肿瘤中 PRMT7 和 PRMT3 上调，PRMT2 和 JMJD6 下调。此外，在 TCGA 分析中，PRMT7 水平随着分期和分级的进展而降低。在患者队列中，与非肿瘤性组织相比，PRMTs 和 JMJD6 在 PCa 中均过度表达，并且核 PRMT2 和 JMJD6 在淋巴结转移中也上调。PRMT7 和 JMJD6 的表达随着分期的进展而上调，并且随着分级的升高，JMJD6 也增加。在去势治疗后，与未经治疗的肿瘤相比，核表达的 PRMT7 和 JMJD6 升高。PRMT2、PRMT7 和 JMD6 也与 EMT 标志物和细胞周期调节剂相关。最后，我们的研究结果表明 PRMTs 和 JMJD6 参与了前列腺癌的进展，并揭示了 PRMTs 与 EMT 介质之间的潜在相互作用，强调了在前列腺癌中靶向精氨酸甲基化的治疗需求。
