Institute of Pathology, University of Regensburg, Germany.
Eur J Cancer. 2013 Apr;49(6):1305-13. doi: 10.1016/j.ejca.2012.11.026. Epub 2012 Dec 19.
Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma. MTA affects cellular signalling, proliferation and migration not only of cancer but also surrounding cells including lymphocytes and stromal fibroblasts. The mode of action of MTA is still not known. Interestingly, MTA is a known potent inhibitor of protein arginine methyltransferases (PRMTs) and is used as a tool in studying activity and impact of PRMTs. This study aimed at analysing PRMTs in melanoma and the potential impact of MTA on tumourigenesis. Our findings demonstrate that expression of PRMT4/CARM1 and PRMT6 is deregulated in melanoma, whereas expression of the remaining PRMTs stays unchanged. General PRMT activity and, consequently, symmetric and asymmetric protein methylation are reduced significantly in melanoma cells and tissues. This is due to a loss of MTAP expression and accumulation of MTA. Reduction of protein methylation by MTA affects cell signalling and leads, for example, to an activation of extracellular signal-regulated kinase (ERK) activity. The effects of endogeneous MTA on PRMTs as presented in this study can strongly support the migratory and invasive phenotype of melanoma cells.
甲基硫腺苷磷酸化酶（MTAP）表达缺失和 5'-甲基硫腺苷（MTA）的积累是多种肿瘤实体的特征，包括恶性黑色素瘤。MTA 不仅影响癌细胞的信号转导、增殖和迁移，还影响包括淋巴细胞和基质成纤维细胞在内的周围细胞。MTA 的作用机制尚不清楚。有趣的是，MTA 是一种已知的强效蛋白精氨酸甲基转移酶（PRMTs）抑制剂，被用作研究 PRMTs 活性和影响的工具。本研究旨在分析黑色素瘤中的 PRMTs 以及 MTA 对肿瘤发生的潜在影响。我们的研究结果表明，PRMT4/CARM1 和 PRMT6 的表达在黑色素瘤中失调，而其余 PRMTs 的表达保持不变。黑色素瘤细胞和组织中的 PRMT 总活性以及对称和非对称蛋白甲基化显著降低。这是由于 MTAP 表达缺失和 MTA 积累所致。MTA 对蛋白质甲基化的减少会影响细胞信号转导，并导致例如细胞外信号调节激酶（ERK）活性的激活。本研究中呈现的内源性 MTA 对 PRMTs 的影响可以强烈支持黑色素瘤细胞的迁移和侵袭表型。
