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NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression

Oncogene volume 37, pages 4887–4900 (2018)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by The National Key Scientific Programme of China (2016YFC1302305), The National Natural Science Foundation of China (81672609, 31671299, 81502282, 81472494,) and the Shenzhen Development and Reform Commission Subject Construction Project [2017] 1434. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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  1. These authors contributed equally: Sheng Tan, Hua Li, Weijie Zhang.

Authors and Affiliations

  1. Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China

    Sheng Tan, Weijie Zhang, Yunying Shao, Yuan Liu, Haiyang Guan, Junsong Zhao, Qing Yu, Min Zhang, Wenchang Qian, Yong Zhu, Huayong Cai & Tao Zhu

  2. School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, China

    Hua Li, Jun Wu, Yani Kang & Yunzhao Gu

  3. Department of Pathology, Anhui Medical University, Meishan Road, Hefei, Anhui, 230031, China

    Keshuo Ding

  4. First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Meishan Road, Hefei, Anhui, 230031, China

    Changyu Chen

  5. Tsinghua-Berkeley Shenzhen Institute, Precision Medicine & Healthcare Research Center, Tsinghua University, Shenzhen, 518055, China

    Peter E. Lobie

  6. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Xiaodong Zhao & Jielin Sun

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  1. Sheng Tan
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Correspondence to Xiaodong Zhao, Jielin Sun or Tao Zhu.

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Tan, S., Li, H., Zhang, W. et al. NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene 37, 4887–4900 (2018). https://doi.org/10.1038/s41388-018-0280-6

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