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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Protein arginine methyl transferase 1– and Jumonji C domain‐containing protein 6–dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice
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Protein arginine methyl transferase 1– and Jumonji C domain‐containing protein 6–dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice

机译：蛋白质精氨酸甲基转移酶1-和Jumonji C域的蛋白6依赖性精氨酸甲基化调节肝细胞核因子4α表达和小鼠的肝细胞增殖

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Alcohol is a well‐established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain‐containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair‐fed mice. Using hepatocyte‐specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol‐fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol‐associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. Conclusion: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (H epatology 2018;67:1109–1126)
机译：酒精是肝细胞癌（HCC）的良好危险因素，但它促进肝癌的机制也不太了解。几项研究表明，细胞蛋白质精氨酸甲基化被醇抑制。通过蛋白质精氨酸甲基转移酶的往复活性来控制精氨酸甲基化，主要是蛋白质精氨酸甲基转移酶1（PRMT1）和含去甲基酶Jumonji C域的蛋白质6（JMJD6）。本研究的目的是探讨精氨酸甲基化变化在醇发病机制中的作用。我们发现，与一对喂食小鼠相比，用酒精喂养的小鼠的小鼠中抑制了PRMT1活性。使用特异性肝细胞的PRMT1敲除小鼠，我们发现PRMT1的损失导致增强的肝细胞增殖和肝脏大小增加33％。这种增加的肝细胞增殖与肝细胞核因子4α（HNF4α）的表达减少有关，是肝脏肿瘤的重要调节剂。我们发现PRMT1通过（HNF4α）启动子的精氨酸甲基化直接调节HNF4α表达。在没有PRMT1的情况下，JMJD6可以将HNF4α启动子移除并抑制其表达。我们能够恢复HNF4α的表达，并在PRMT1敲除小鼠中取消JMJD6敲低的肝细胞增殖的增加。 JMJD6在醇喂食小鼠中的敲低类似地增加了HNF4α表达。然后，我们检查了精氨酸甲基化的丧失是否可能在酒精相关的肝癌中发挥作用。我们检查了25个人HCC标本，发现在这些样本中的精氨酸甲基化水平和HNF4α表达之间的强相关（R = 0.8; p <0.01），表明上述机制在患者中是相关的。结论：携带，这些数据表明，PRMT1抑制如酒精诱导，可能导致表观遗传变化导致HNF4α的丧失。这种效果可能有助于饮酒促进肝脏肿瘤的能力。 （2018年Hopatology; 67：1109-1126）

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