Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that ‘reads’ methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC.

中文翻译：

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SND1甲基精氨酸阅读器功能的丧失赋予对肝细胞癌的抵抗力

葡萄球菌核酸酶 Tudor 结构域包含 1 (SND1) 蛋白是一种癌基因，可通过其 Tudor 结构域“读取”甲基精氨酸标记。具体来说，它识别蛋白质精氨酸甲基转移酶 5 (PRMT5) 沉积的甲基化标记，众所周知，精氨酸甲基转移酶 5 也会促进肿瘤发生。尽管SND1可以驱动肝细胞癌(HCC)，但尚不清楚SND1 Tudor结构域是否需要促进HCC。我们试图通过开发两种基因工程 SND1 小鼠模型来确定 SND1 Tudor 结构域在正常和致瘤环境中的生物学作用，即 Snd1 敲除 (Snd1 KO) 和 Snd1 Tudor 结构域突变 (Snd1 KI) 小鼠，其突变型 SND1 可以不再识别 PRMT5 催化的甲基精氨酸标记。对正常、KO 和 KI 肝脏样本的定量 PCR 分析揭示了 SND1 Tudor 结构域在调节主要急性期蛋白编码基因表达中的作用，这可以为肿瘤环境中 SND1 功能提供机制见解。先前的研究表明，小鼠肝脏中 SND1 的异位过度表达会显着加速二乙基亚硝胺 (DEN) 诱导的 HCC 的发展。因此，我们测试了 DEN 和 SND1 缺失或突变对 HCC 发展的综合影响。我们发现，Snd1 KO 和 Snd1 KI 小鼠在暴露于 DEN 后都受到部分保护，免受恶性肿瘤的发展。这些结果支持开发针对 SND1 Tudor 结构域的小分子抑制剂或使用上游 PRMT5 抑制剂作为 HCC 的新疗法。