Ichikawa Tomonaga, Suekane Akira, Nakahata Shingo, Iha Hidekatsu, Shimoda Kazuya, Murakami Takashi, Morishita Kazuhiro
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1692, Japan.
Department of Microbiology, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan.
Int J Mol Sci. 2024 Feb 29;25(5):2842. doi: 10.3390/ijms25052842.
N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2 ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2 tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2 ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2 cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2 ATL.
N-myc下游调控基因2（NDRG2）是一种肿瘤抑制因子，在包括成人T细胞白血病/淋巴瘤（ATL）在内的多种肿瘤中经常缺失。NDRG2表达的下调通过几种重要信号分子的异常磷酸化参与肿瘤进展。我们观察到，NDRG2的下调通过丝氨酸335处PRMT5磷酸化增加诱导蛋白质精氨酸甲基转移酶5（PRMT5）从细胞核转移到细胞质。在NDRG2缺失的ATL中，细胞质PRMT5通过精氨酸甲基化增强HSP90A伴侣活性，导致肿瘤进展和致癌客户蛋白的维持。因此，我们研究了抑制PRMT5活性是否是NDRG2肿瘤的药物靶点。敲低PRMT5及其结合伴侣甲基化蛋白50（MEP50）的表达显著证明了通过降解NDRG2缺失的ATL细胞中的AKT和NEMO来抑制细胞增殖，而表达NDRG2的细胞不会损害客户蛋白的稳定性。我们认为，PRMT5/MEP50与NDRG2下调之间的关系可能表现出一种新的脆弱性和治疗靶点。通过抑制HSP90精氨酸甲基化以及客户蛋白的降解，PRMT5特异性抑制剂CMP5和HLCL61对NDRG2缺失的癌细胞比表达NDRG2的细胞更敏感。因此，干扰PRMT5活性已成为促进NDRG2缺失的ATL中癌症易感性的一种可行且有效的策略。
