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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Hepatocellular Carcinoma | Research

CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression

Authors: Sheng Tan, Ming Zhang, Xinglong Shi, Keshuo Ding, Qiang Zhao, Qianying Guo, Hao Wang, Zhengsheng Wu, Yani Kang, Tao Zhu, Jielin Sun, Xiaodong Zhao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

Alternative polyadenylation (APA) is an important mechanism of gene expression regulation through generation of RNA isoforms with distinct 3′ termini. Increasing evidence has revealed that APA is actively involved in development and disease, including hepatocellular carcinoma (HCC). However, how APA functions in tumor formation and progression remains elusive. In this study, we investigated the role of cleavage factor I (CFIm) subunit CPSF6 in human hepatocellular carcinoma (HCC).

Methods

Expression levels of CPSF6 in clinical tissues and cell lines were determined by qRT-PCR and western blot. Functional assays, including the cell number, MTT, colony formation and transwell, were used to determine the oncogenic role of CPSF6 in HCC. Animal experiments were used to determine the role of CPSF6 in HCC tumorigenicity in vivo. Deep sequencing-based 3 T-seq was used to profile the transcriptome-wide APA sites in both HCC cells and CPSF6 knockdown HCC cells. The function of CPSF6-affected target NQO1 with distinct 3′UTRs was characterized by metabolism assays.

Results

We observed CPSF6 was upregulated in HCC and the high expression of CPSF6 was associated with poor prognosis in patients. Overexpression of CPSF6 promoted proliferation, migration and invasion of HCC cells in vitro and in vivo. Transcriptome-wide APA profiling analysis indicated that high expression of CPSF6 promoted the favorable usage of the proximal poly(A) site in the 3′UTR of NQO1. We demonstrated CPSF6-induced tumorigenic activities were mediated by the NQO1 isoform with short 3′UTR. Furthermore, we found that CPSF6 induced metabolic alterations in liver cells through NQO1.

Conclusion

CPSF6 plays a critical role in HCC progression by upregulating NQO1 expression through APA. These findings provide evidence to demonstrate that APA of NQO1 contributes to HCC progression and may have implications for developing new therapeutic strategy against this disease.
Appendix
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Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRefPubMed
2.
Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.PubMedCrossRef
3.
Marengo A, Rosso C, Bugianesi E. Liver Cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17.PubMedCrossRef
4.
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604.PubMedPubMedCentralCrossRef
5.
Craig AJ, von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A. Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2020;17(3):139–52.PubMedCrossRef
6.
7.
Tian B, Manley JL. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol. 2017;18(1):18–30.PubMedCrossRef
8.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610.PubMedCrossRef
9.
10.
Hentze MW, Castello A, Schwarzl T, Preiss T. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol. 2018;19(5):327–41.PubMedCrossRef
11.
12.
Elkon R, Ugalde AP, Agami R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet. 2013;14(7):496–506.PubMedCrossRef
13.
Gruber AJ, Zavolan M. Alternative cleavage and polyadenylation in health and disease. Nat Rev Genet. 2019;20(10):599–614.PubMedCrossRef
14.
Mayr C. Evolution and biological roles of alternative 3'UTRs. Trends Cell Biol. 2016;26(3):227–37.PubMedCrossRef
15.
Masamha CP, Wagner EJ. The contribution of alternative polyadenylation to the cancer phenotype. Carcinogenesis. 2018;39(1):2–10.PubMedCrossRef
16.
17.
Mayr C, Bartel DP. Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell. 2009;138(4):673–84.PubMedPubMedCentralCrossRef
18.
Lin Y, Li Z, Ozsolak F, Kim SW, Arango-Argoty G, Liu TT, Tenenbaum SA, Bailey T, Monaghan AP, Milos PM, et al. An in-depth map of polyadenylation sites in cancer. Nucleic Acids Res. 2012;40(17):8460–71.PubMedPubMedCentralCrossRef
19.
Xiang Y, Ye Y, Lou Y, Yang Y, Cai C, Zhang Z, Mills T, Chen NY, Kim Y, Muge Ozguc F, et al. Comprehensive characterization of alternative Polyadenylation in human Cancer. J Natl Cancer Inst. 2018;110(4):379–89.PubMedCrossRef
20.
Xia Z, Donehower LA, Cooper TA, Neilson JR, Wheeler DA, Wagner EJ, Li W. Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types. Nat Commun. 2014;5:5274.PubMedCrossRef
21.
22.
Masamha CP, Xia Z, Yang J, Albrecht TR, Li M, Shyu AB, Li W, Wagner EJ. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature. 2014;510(7505):412–6.PubMedPubMedCentralCrossRef
23.
Chen X, Zhang JX, Luo JH, Wu S, Yuan GJ, Ma NF, Feng Y, Cai MY, Chen RX, Lu J, et al. CSTF2-induced shortening of the RAC1 3'UTR promotes the pathogenesis of Urothelial carcinoma of the bladder. Cancer Res. 2018;78(20):5848–62.PubMed
24.
Lai DP, Tan S, Kang YN, Wu J, Ooi HS, Chen J, Shen TT, Qi Y, Zhang X, Guo Y, et al. Genome-wide profiling of polyadenylation sites reveals a link between selective polyadenylation and cancer metastasis. Hum Mol Genet. 2015;24(12):3410–7.PubMedCrossRef
25.
Tan S, Li H, Zhang W, Shao Y, Liu Y, Guan H, Wu J, Kang Y, Zhao J, Yu Q, et al. NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene. 2018;37(35):4887–900.PubMedCrossRef
26.
Ruegsegger U, Beyer K, Keller W. Purification and characterization of human cleavage factor Im involved in the 3′ end processing of messenger RNA precursors. J Biol Chem. 1996;271(11):6107–13.PubMedCrossRef
27.
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 U S A. 2010;107(22):10062–7.PubMedPubMedCentralCrossRef
28.
Kim S, Yamamoto J, Chen Y, Aida M, Wada T, Handa H, Yamaguchi Y. Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation. Genes Cells. 2010;15(9):1003–13.PubMedCrossRef
29.
Zhu Y, Wang X, Forouzmand E, Jeong J, Qiao F, Sowd GA, Engelman AN, Xie X, Hertel KJ, Shi Y. Molecular mechanisms for CFIm-mediated regulation of mRNA alternative Polyadenylation. Mol Cell. 2018;69(1):62–74 e64.PubMedCrossRef
30.
Ruegsegger U, Blank D, Keller W. Human pre-mRNA cleavage factor Im is related to spliceosomal SR proteins and can be reconstituted in vitro from recombinant subunits. Mol Cell. 1998;1(2):243–53.PubMedCrossRef
31.
Brown KM, Gilmartin GM. A mechanism for the regulation of pre-mRNA 3′ processing by human cleavage factor Im. Mol Cell. 2003;12(6):1467–76.PubMedCrossRef
32.
Binothman N, Hachim IY, Lebrun JJ, Ali S. CPSF6 is a clinically relevant breast Cancer vulnerability target: role of CPSF6 in breast Cancer. EBioMedicine. 2017;21:65–78.PubMedPubMedCentralCrossRef
33.
34.
Fu Y, Sun Y, Li Y, Li J, Rao X, Chen C, Xu A. Differential genome-wide profiling of tandem 3′ UTRs among human breast cancer and normal cells by high-throughput sequencing. Genome Res. 2011;21(5):741–7.PubMedPubMedCentralCrossRef
35.
Wang R, Nambiar R, Zheng D, Tian B. PolyA_DB 3 catalogs cleavage and polyadenylation sites identified by deep sequencing in multiple genomes. Nucleic Acids Res. 2018;46(D1):D315–9.PubMedCrossRef
36.
Rahman R, Hammoud GM, Almashhrawi AA, Ahmed KT, Ibdah JA. Primary hepatocellular carcinoma and metabolic syndrome: an update. World J Gastrointest Oncol. 2013;5(9):186–94.PubMedPubMedCentralCrossRef
37.
Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol. 2019;16(12):748–66.PubMedCrossRef
38.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, et al. Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131(6):1109–23.PubMedCrossRef
39.
Fang Y, Xue JL, Shen Q, Chen J, Tian L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 2012;55(6):1852–62.PubMedCrossRef
40.
Sun X, Dai G, Yu L, Hu Q, Chen J, Guo W. miR-143-3p inhibits the proliferation, migration and invasion in osteosarcoma by targeting FOSL2. Sci Rep. 2018;8(1):606.PubMedPubMedCentralCrossRef
41.
Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, Zheng X. miR-34a inhibits migration and invasion by down-regulation of c-met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009;275(1):44–53.PubMedCrossRef
42.
Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact. 2000;129(1–2):77–97.PubMedCrossRef
43.
Fang S, Zhang D, Weng W, Lv X, Zheng L, Chen M, Fan X, Mao J, Mao C, Ye Y, et al. CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway. Biochim Biophys Acta Mol Cell Res. 1867;2020(2):118624.CrossRef
44.
Yang Y, Zhang Y, Wu Q, Cui X, Lin Z, Liu S, Chen L. Clinical implications of high NQO1 expression in breast cancers. J Exp Clin Cancer Res. 2014;33:14.PubMedPubMedCentralCrossRef
45.
Thapa D, Meng P, Bedolla RG, Reddick RL, Kumar AP, Ghosh R. NQO1 suppresses NF-kappaB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis. Cancer Res. 2014;74(19):5644–55.PubMedPubMedCentralCrossRef
46.
Li WY, Zhou HZ, Chen Y, Cai XF, Tang H, Ren JH, Wai Wong VK, Kwan Law BY, Chen Y, Cheng ST, et al. NAD(P)H: Quinone oxidoreductase 1 overexpression in hepatocellular carcinoma potentiates apoptosis evasion through regulating stabilization of X-linked inhibitor of apoptosis protein. Cancer Lett. 2019;451:156–67.PubMedCrossRef
47.
Li Z, Zhang Y, Jin T, Men J, Lin Z, Qi P, Piao Y, Yan G. NQO1 protein expression predicts poor prognosis of non-small cell lung cancers. BMC Cancer. 2015;15:207.PubMedPubMedCentralCrossRef
48.
Kandala DT, Mohan N, A V, A PS, G R, Laishram RS. CstF-64 and 3′-UTR cis-element determine star-PAP specificity for target mRNA selection by excluding PAPalpha. Nucleic Acids Res. 2016;44(2):811–23.PubMedCrossRef
49.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11–20.CrossRefPubMed
50.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedPubMedCentralCrossRef
51.
Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.PubMedCrossRef
52.
De Matteis S, Ragusa A, Marisi G, De Domenico S, Casadei Gardini A, Bonafe M, Giudetti AM. Aberrant metabolism in hepatocellular carcinoma provides diagnostic and therapeutic opportunities. Oxidative Med Cell Longev. 2018;2018:7512159.CrossRef
53.
Piccinin E, Villani G, Moschetta A. Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators. Nat Rev Gastroenterol Hepatol. 2019;16(3):160–74.PubMedCrossRef
54.
Dimri M, Humphries A, Laknaur A, Elattar S, Lee TJ, Sharma A, Kolhe R, Satyanarayana A. NAD(P) H Quinone dehydrogenase 1 ablation inhibits activation of the Phosphoinositide 3-kinase/Akt serine/threonine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways and blocks metabolic adaptation in hepatocellular carcinoma. Hepatology. 2020;71(2):549–68.PubMedCrossRef
Metadata
Title
CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression
Authors
Sheng Tan
Ming Zhang
Xinglong Shi
Keshuo Ding
Qiang Zhao
Qianying Guo
Hao Wang
Zhengsheng Wu
Yani Kang
Tao Zhu
Jielin Sun
Xiaodong Zhao
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01884-z

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