SND1甲基精氨酸读写器功能的丧失赋予了对肝细胞癌的耐药性。

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2023-11-29 DOI:10.1042/BCJ20230384
Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford
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引用次数: 0

摘要

含有1(SND1)蛋白的葡萄球菌核酸酶都铎结构域是一种通过其都铎结构区“读取”甲基精氨酸标记的致癌基因。具体来说,它识别精氨酸甲基转移酶5(PRMT5)蛋白沉积的甲基化标记,众所周知,PRMT5蛋白也能促进肿瘤发生。尽管SND1可以驱动肝细胞癌(HCC),但尚不清楚是否需要SND1都铎结构域来促进HCC。我们试图通过开发两种基因工程SND1小鼠模型,即SND1敲除(SND1 KO)和SND1都铎结构域突变(SND1 KI)小鼠来确定SND1都铎结构区在正常和致瘤环境中的生物学作用,其突变体SND1不再能识别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都铎结构域在调节编码主要急性期蛋白的基因表达中的作用,这可以为SND1在肿瘤环境中的功能提供机制见解。先前的研究表明,小鼠肝脏中SND1的异位过表达显著加速了二乙基亚硝胺(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发展的联合作用。我们发现,暴露于DEN后,Snd1 KO和Snd1 KI小鼠对恶性肿瘤的发展都有部分保护作用。这些结果支持开发靶向SND1都铎结构域的小分子抑制剂或使用上游PRMT5抑制剂作为HCC的新治疗方法。
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Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.

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.

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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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