Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.

中文翻译：

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NUDT21通过交替的多腺苷酸化负调控PSMB2和CXXC5，并有助于抑制肝细胞癌。

替代性聚腺苷酸化（APA）是一种重要的转录后调控机制，涉及多种疾病，包括癌症。CFIm25是NUDT21编码的切割因子I的亚基，是3'RNA切割和聚腺苷酸化所必需的。尽管最近据报道它参与了胶质母细胞瘤的肿瘤抑制，但在其他类型的癌症中其作用和潜在的功能机制仍不清楚。在这项研究中，我们表征了NUDT21在肝细胞癌（HCC）中的特征。与相邻的非肿瘤区室相比，在肝癌组织中观察到NUDT21的表达降低。NUDT21表达较低的HCC患者术后术后的总生存时间和无病生存时间要短于NUDT21表达较高的患者。减少NUDT21可以促进HCC细胞增殖，转移和肿瘤发生，而NUDT21的强制表达则表现出相反的效果。然后，我们在HCC细胞中进行了全球APA位点分析，并发现了在NUDT21表达调节后3'UTR缩短的可观基因。特别是，我们进一步表征了NUDT21调控的基因PSMB2和CXXC5。我们发现NUDT21敲低会增加PSMB2和CXXC5 3'UTR中近端聚腺苷酸化位点的使用，从而导致PSMB2和CXXC5表达的显着增加。此外，敲低PSMB2或CXXC5可抑制HCC细胞增殖和侵袭。综上所述，我们的研究表明NUDT21至少部分通过抑制PSMB2和CXXC5抑制HCC增殖，转移和肿瘤发生，