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.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96–108.
Naga ChP, Gurram L, Chopra S, Mahantshetty U. The management of locally advanced cervical cancer. Curr Opin Oncol. 2018;30:323–9.
Friedlander M, Grogan M, Force USPST. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002;7:342–7.
Elit LM, Hirte H. Management of advanced or recurrent cervical cancer: chemotherapy and beyond. Expert Rev Anticancer Ther. 2014;14:319–32.
Lareau LF, Green RE, Bhatnagar RS, Brenner SE. The evolving roles of alternative splicing. Curr Opin Struct Biol. 2004;14:273–82.
Wu X, Liu M, Downie B, Liang C, Ji G, Li QQ, et al. Genome-wide landscape of polyadenylation in Arabidopsis provides evidence for extensive alternative polyadenylation. Proc Natl Acad Sci USA. 2011;108:12533–8.
Erson-Bensan AE. Alternative polyadenylation and RNA-binding proteins. J Mol Endocrinol. 2016;57:F29–34.
Ma L, Guo C, Li QQ. Role of alternative polyadenylation in epigenetic silencing and antisilencing. Proc Natl Acad Sci USA. 2014;111:9–10.
Gruber AJ, Zavolan M. Alternative cleavage and polyadenylation in health and disease. Nat Rev Genet. 2019;20:599–614.
Creemers EE, Bawazeer A, Ugalde AP, van Deutekom HW, van der Made I, de Groot NE, et al. Genome-wide polyadenylation maps reveal dynamic mRNA 3’-end formation in the failing human heart. Circulation Res. 2016;118:433–8.
Martinez FJ, Pratt GA, Van Nostrand EL, Batra R, Huelga SC, Kapeli K, et al. Protein-RNA networks regulated by normal and ALS-associated mutant HNRNPA2B1 in the nervous system. Neuron. 2016;92:780–95.
Weng T, Ko J, Masamha CP, Xia Z, Xiang Y, Chen NY, et al. Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation. J Clin Investig. 2019;129:1984–99.
Brumbaugh J, Di Stefano B, Wang X, Borkent M, Forouzmand E, Clowers KJ, et al. Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling. Cell. 2018;172:106–20 e21.
Yang Q, Gilmartin GM, Doublie S. Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3’ processing. Proc Natl Acad Sci USA. 2010;107:10062–7.
Masamha CP, Wagner EJ. The contribution of alternative polyadenylation to the cancer phenotype. Carcinogenesis. 2018;39:2–10.
Jafari Najaf Abadi MH, Shafabakhsh R, Asemi Z, Mirzaei HR, Sahebnasagh R, Mirzaei H, et al. CFIm25 and alternative polyadenylation: conflicting roles in cancer. Cancer Lett. 2019;459:112–21.
Li X, Ding J, Wang X, Cheng Z, Zhu Q. NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. Oncogene. 2020;39:891–904.
Masamha CP, Xia Z, Yang J, Albrecht TR, Li M, Shyu AB, et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature. 2014;510:412–6.
Chu Y, Elrod N, Wang C, Li L, Chen T, Routh A, et al. Nudt21 regulates the alternative polyadenylation of Pak1 and is predictive in the prognosis of glioblastoma patients. Oncogene. 2019;38:4154–68.
Sun M, Ding J, Li D, Yang G, Cheng Z, Zhu Q. NUDT21 regulates 3’-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. Cancer Lett. 2017;410:158–68.
Zhang L, Zhang W. Knockdown of NUDT21 inhibits proliferation and promotes apoptosis of human K562 leukemia cells through ERK pathway. Cancer Manag Res. 2018;10:4311–23.
Katoh M, Katoh M. AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis. Int J Mol Med. 2007;19:699–703.
Li S, Deng P, Wang M, Liu X, Jiang M, Jiang B, et al. IL-1alpha and IL-1beta promote NOD2-induced immune responses by enhancing MAPK signaling. Lab Investig. 2019;99:1321–34.
Singh AK, Fechtner S, Chourasia M, Sicalo J, Ahmed S. Critical role of IL-1alpha in IL-1beta-induced inflammatory responses: cooperation with NF-kappaBp65 in transcriptional regulation. FASEB J. 2019;33:2526–36.
Song Z, Lin Y, Ye X, Feng C, Lu Y, Yang G, et al. Expression of IL-1alpha and IL-6 is associated with progression and prognosis of human cervical cancer. Med Sci Monit. 2016;22:4475–81.
Pu Y, Zhang Z, Zhou B, Chen P, Zhang K, Song Y, et al. Association of an insertion/deletion polymorphism in IL1A 3’-UTR with risk for cervical carcinoma in Chinese Han Women. Hum Immunol. 2014;75:740–4.
Husseinzadeh N, Davenport SM. Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review. Gynecologic Oncol. 2014;135:359–63.
Wang W, Yang C, Nie H, Qiu X, Zhang L, Xiao Y, et al. LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk. Int J Cancer. 2019;144:1345–55.
Morale MG, da Silva Abjaude W, Silva AM, Villa LL, Boccardo E. HPV-transformed cells exhibit altered HMGB1-TLR4/MyD88-SARM1 signaling axis. Sci Rep. 2018;8:3476.
Lou JC, Lan YL, Gao JX, Ma BB, Yang T, Yuan ZB, et al. Silencing NUDT21 attenuates the mesenchymal identity of glioblastoma cells via the NF-kappaB pathway. Front Mol Neurosci. 2017;10:420.
Shang C, Wang W, Liao Y, Chen Y, Liu T, Du Q, et al. LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism. Cancer Res. 2018;78:877–90.
Jin J, Zhang Z, Zhang S, Chen X, Chen Z, Hu P, et al. Fatty acid binding protein 4 promotes epithelial-mesenchymal transition in cervical squamous cell carcinoma through AKT/GSK3beta/Snail signaling pathway. Mol Cell Endocrinol. 2018;461:155–64.
Martinez-Reyes I, Chandel NS. Acetyl-CoA-directed gene transcription in cancer cells. Genes Dev. 2018;32:463–5.
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105:103–4.
The study was supported by the National Natural Science Foundation of China (Grant no. 81772714; 81402303).
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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