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Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation

Abstract

Nudix Hydrolase 21 (NUDT21), an alternative polyadenylation (APA)-regulatory protein, exhibits tumor-suppressive effects. However, its role in cervical cancer (CxCa) remains unknown. In the present study, we found that NUDT21 expression was reduced in CxCa tissues and cells, and NUDT21 levels were highly associated with the clinical prognosis of patients with CxCa. Knockdown of NUDT21 promoted CxCa cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and lung metastasis in vivo. Overexpression of NUDT21 produces the opposite effects. Moreover, we performed polyadenylation site sequencing (PAS-Seq) and identified 457 transcripts with lengthened 3′ untranslated regions (3′ UTRs) upon NUDT21 overexpression. In particular, NUDT21 modulated the expression of several genes involved in fatty acid metabolism and the Wnt and NF-κB signaling pathways in CxCa development. Taken together, our study demonstrated that the APA regulatory effect of NUDT21 is an important mechanism for CxCa suppression.

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Fig. 1: NUDT21 inhibits the aggressiveness of CxCa cells in vitro.
Fig. 2: NUDT21 suppresses tumorigenicity and metastasis of CxCa in vivo.
Fig. 3: PAS-Seq of NUDT21 overexpression vs. control in CxCa cells.
Fig. 4: NUDT21 regulates the length of the 3′ UTRs of WNT10B, IL-1A, HMGB1, and ACAT2 genes.
Fig. 5: WNT10B, IL-1A, HMGB1, and ACAT2 modulate the activity of Wnt and NF-κB signaling pathways, and fatty acid metabolism in CxCa development.
Fig. 6: NUDT21 suppresses lipid biosynthesis and the Wnt/β-catenin and NF-κB signaling pathways.
Fig. 7: Clinical relevance of NUDT21 mediation of Wnt/β-catenin and NF-κB signaling in CxCa.

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Acknowledgements

The study was supported by the National Natural Science Foundation of China (Grant no. 81772714; 81402303).

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Correspondence to Yaqiong Liu or Teng Hou.

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Xing, Y., Chen, L., Gu, H. et al. Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation. Oncogene 40, 2051–2064 (2021). https://doi.org/10.1038/s41388-021-01693-w

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