BACKGROUND AIMS Pseudouridine is a prevalent RNA modification and is highly present in the serum and urine of patients with hepatocellular carcinoma (HCC). However, the role of pseudouridylation and its modifiers in HCC remains unknown. We investigated the function and underlying mechanism of pseudouridine synthase 1 (PUS1) in HCC. APPROACH RESULTS By analyzing the TCGA data set, PUS1 was found significantly upregulated in human HCC specimens and positively correlated with tumor grade and poor prognosis of HCC. Knockdown of PUS1 inhibited cell proliferation and the growth of tumors in subcutaneous xenograft mouse model. Accordingly, increased cell proliferation, and tumor growth were observed in PUS1 overexpressing cells. Furthermore, overexpression of PUS1 significantly accelerates tumor formation in a mouse HCC model established by hydrodynamic tail vein injection, while knock-out of PUS1 decreased it. Additionally, PUS1 catalytic activity is required for HCC tumorigenesis. Mechanistically, we profiled the mRNA targets of PUS1 by utilizing Surveying Targets by APOBEC1-Mediated Profiling (STAMP) and found that PUS1 incorporated pseudouridine into mRNAs of a set of oncogenes, thereby endowing them with greater translation capacity. CONCLUSION Our study highlights the critical role of PUS1 and pseudouridylation in HCC development, and provides new insight that PUS1 enhances the protein levels of a set of oncogenes, including IRS1 and c-MYC, via pseudouridylation-mediated mRNA translation.

中文翻译：

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PUS1 通过 mRNA 假尿苷化增强致癌 mRNA 的翻译来促进肝细胞癌。

背景目的 假尿苷是一种常见的 RNA 修饰，在肝细胞癌 (HCC) 患者的血清和尿液中高度存在。然而，假尿苷化及其修饰剂在 HCC 中的作用仍不清楚。我们研究了 HCC 中假尿苷合酶 1 (PUS1) 的功能和潜在机制。方法结果通过分析 TCGA 数据集，发现 PUS1 在人类 HCC 标本中显着上调，并与 HCC 的肿瘤分级和不良预后呈正相关。PUS1 的敲低抑制了皮下异种移植小鼠模型中的细胞增殖和肿瘤生长。因此，在 PUS1 过表达细胞中观察到细胞增殖增加和肿瘤生长。此外，在通过尾静脉注射建立的小鼠肝癌模型中，PUS1的过表达显着加速了肿瘤的形成，而PUS1的敲除则减少了肿瘤的形成。此外，PUS1 催化活性是 HCC 肿瘤发生所必需的。从机制上讲，我们利用 APOBEC1 介导分析 (STAMP) 的调查目标对 PUS1 的 mRNA 目标进行了分析，发现 PUS1 将假尿苷整合到一组癌基因的 mRNA 中，从而赋予它们更大的翻译能力。结论 我们的研究强调了 PUS1 和假尿苷化在 HCC 发展中的关键作用，并提供了新的见解，即 PUS1 通过假尿苷化介导的 mRNA 翻译增强了一组癌基因（包括 IRS1 和 c-MYC）的蛋白质水平。