USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo

Yuan,Xianwen; Sun,Xitai; Shi,Xiaolei; Jiang,Chunping; Yu,Decai; Zhang,Weiwei; Guan,Wenxian; Zhou,Jianxin; Wu,Yafu; Qiu,Yudong; Ding,Yitao

doi:10.3892/or.2015.4065

USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo

Authors:
- Xianwen Yuan
- Xitai Sun
- Xiaolei Shi
- Chunping Jiang
- Decai Yu
- Weiwei Zhang
- Wenxian Guan
- Jianxin Zhou
- Yafu Wu
- Yudong Qiu
- Yitao Ding
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Affiliations: Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China, Department of General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
Published online on: June 15, 2015 https://doi.org/10.3892/or.2015.4065
Pages: 823-832

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Abstract

Ubiquitin specific protease 39 (USP39) plays an important role in mRNA splicing. In the present study, we investigated the role of USP39 in regulating the growth of hepatocellular carcinoma (HCC). We detected USP39 expression in more than 100 HCC clinical samples. The USP39 expression was significantly higher in the tumor tissues compared to the adjacent normal tissues, and was strongly associated with the pathological grade of HCC. USP39 knockdown inhibited cell proliferation and colony formation in vitro in the HepG2 cells, while upregulation of USP39 promoted tumor cell growth. FCM assay showed that USP39 knockdown led to G2/M arrest and induced apoptosis in the HepG2 cells. USP39 knockdown by shRNA inhibited xenograft tumor growth in nude mice. Moreover, USP39 knockdown led to the upregulation of p-Cdc2 and downregulation of p-Cdc25c and p-myt1, while the expression of total Cdc2, Cdc25c and myt1 was not changed in the USP39-knockdown cells. We also found that p-Cdc2 was decreased in the USP39-overexpressing cells and was upregulated in the xenografted tumors derived from the HepG2/KD cells from nude mice. Meanwhile, the expression levels of FoxM1 and its target genes PLK1 and cyclin B1 were decreased in the USP39-knockdown cells. These results suggest that USP39 may contribute to FoxM1 splicing in HCC tumor cells. Our data indicate that USP39 knockdown inhibited the growth of HCC both in vitro and in vivo through G2/M arrest, which was partly achieved via the inhibition of FoxM1 splicing.

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1	Villanueva A, Minguez B, Forner A, Reig M and Llovet JM: Hepatocellular carcinoma: Novel molecular approaches for diagnosis, prognosis, and therapy. Annu Rev Med. 61:317–328. 2010. View Article : Google Scholar : PubMed/NCBI
2	Huynh H: Molecularly targeted therapy in hepatocellular carcinoma. Biochem Pharmacol. 80:550–560. 2010. View Article : Google Scholar : PubMed/NCBI
3	Fisher D, Krasinska L, Coudreuse D and Novák B: Phosphorylation network dynamics in the control of cell cycle transitions. J Cell Sci. 125:4703–4711. 2012. View Article : Google Scholar : PubMed/NCBI
4	Nurse P: A long twentieth century of the cell cycle and beyond. Cell. 100:71–78. 2000. View Article : Google Scholar : PubMed/NCBI
5	Martin SJ, McGahon AJ, Nishioka WK, LaFace D, Guo X, Th’ng J, Bradbury EM and Green DR: p34cdc2 and apoptosis. Science. 269:106–107. 1995. View Article : Google Scholar : PubMed/NCBI
6	Laoukili J, Stahl M and Medema RH: FoxM1: At the crossroads of ageing and cancer. Biochim Biophys Acta. 1775:92–102. 2007.
7	Koo CY, Muir KW and Lam EW: FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta. 1819:28–37. 2012. View Article : Google Scholar
8	Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA and Costa RH: Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Mol Cell Biol. 17:1626–1641. 1997.PubMed/NCBI
9	Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T and Costa RH: Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 25:10875–10894. 2005. View Article : Google Scholar : PubMed/NCBI
10	Costa RH: FoxM1 dances with mitosis. Nat Cell Biol. 7:108–110. 2005. View Article : Google Scholar : PubMed/NCBI
11	Nagata A, Igarashi M, Jinno S, Suto K and Okayama H: An additional homolog of the fission yeast cdc25⁺ gene occurs in humans and is highly expressed in some cancer cells. New Biol. 3:959–968. 1991.PubMed/NCBI
12	Galaktionov K and Beach D: Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclins. Cell. 67:1181–1194. 1991. View Article : Google Scholar : PubMed/NCBI
13	Molinari M, Mercurio C, Dominguez J, Goubin F and Draetta GF: Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep. 1:71–79. 2000. View Article : Google Scholar
14	Karlsson C, Katich S, Hagting A, Hoffmann I and Pines J: Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J Cell Biol. 146:573–584. 1999. View Article : Google Scholar : PubMed/NCBI
15	De Souza CP, Ellem KA and Gabrielli BG: Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp Cell Res. 257:11–21. 2000. View Article : Google Scholar : PubMed/NCBI
16	Hoffmann I, Clarke PR, Marcote MJ, Karsenti E and Draetta G: Phosphorylation and activation of human cdc25-C by cdc2-cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 12:53–63. 1993.PubMed/NCBI
17	Perdiguero E and Nebreda AR: Regulation of Cdc25C activity during the meiotic G2/M transition. Cell Cycle. 3:733–737. 2004. View Article : Google Scholar : PubMed/NCBI
18	Reyes-Turcu FE, Ventii KH and Wilkinson KD: Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 78:363–397. 2009. View Article : Google Scholar : PubMed/NCBI
19	van Leuken RJ, Luna-Vargas MP, Sixma TK, Wolthuis RM and Medema RH: Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B. Cell Cycle. 7:2710–2719. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ríos Y, Melmed S, Lin S and Liu NA: Zebrafish usp39 mutation leads to rb1 mRNA splicing defect and pituitary lineage expansion. PLoS Genet. 7:e10012712011. View Article : Google Scholar : PubMed/NCBI
21	Wang H, Ji X, Liu X, Yao R, Chi J, Liu S, Wang Y, Cao W and Zhou Q: Lentivirus-mediated inhibition of USP39 suppresses the growth of breast cancer cells in vitro. Oncol Rep. 30:2871–2877. 2013.PubMed/NCBI
22	Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X and Ding YT: Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World J Gastroenterol. 18:4925–4933. 2012. View Article : Google Scholar : PubMed/NCBI
23	Makarova OV, Makarov EM and Lührmann R: The 65 and 110 kDa SR-related proteins of the U4/U6.U5 tri-snRNP are essential for the assembly of mature spliceosomes. EMBO J. 20:2553–2563. 2001. View Article : Google Scholar : PubMed/NCBI
24	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
25	Lapenna S and Giordano A: Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 8:547–566. 2009. View Article : Google Scholar : PubMed/NCBI
26	Smits VA, Klompmaker R, Vallenius T, Rijksen G, Mäkela TP and Medema RH: p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J Biol Chem. 275:30638–30643. 2000. View Article : Google Scholar : PubMed/NCBI
27	Guadagno TM and Newport JW: Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell. 84:73–82. 1996. View Article : Google Scholar : PubMed/NCBI
28	Atherton-Fessler S, Liu F, Gabrielli B, Lee MS, Peng CY and Piwnica-Worms H: Cell cycle regulation of the p34cdc2 inhibitory kinases. Mol Biol Cell. 5:989–1001. 1994. View Article : Google Scholar : PubMed/NCBI
29	Norbury C, Blow J and Nurse P: Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 10:3321–3329. 1991.PubMed/NCBI
30	McGowan CH and Russell P: Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15. EMBO J. 12:75–85. 1993.PubMed/NCBI
31	Wells NJ, Watanabe N, Tokusumi T, Jiang W, Verdecia MA and Hunter T: The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G(2)/M progression. J Cell Sci. 112:3361–3371. 1999.PubMed/NCBI
32	Cogswell JP, Brown CE, Bisi JE and Neill SD: Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ. 11:615–623. 2000.
33	Dibb M, Han N, Choudhury J, Hayes S, Valentine H, West C, Ang YS and Sharrocks AD: The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma. Br J Cancer. 107:1766–1775. 2012. View Article : Google Scholar : PubMed/NCBI