PUS1 promotes hepatocellular carcinoma via mRNA pseudouridylation to enhance the translation of oncogenic mRNAs
PUS1 promotes hepatocellular carcinoma via mRNA pseudouridylation to enhance the translation of oncogenic mRNAs
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DOI：
10.1097/hep.0000000000000702
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Zhen-Dong Xiao
中科院分区：
文献类型：
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作者：
Yan-Xia Hu;Li-Ting Diao;Ya-Rui Hou;Guo Lv;Shuang Tao;Wan-Yi Xu;Shu-Juan Xie;Ya-Han Ren;Zhen-Dong Xiao
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.
