Open Access

Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics

  • Authors:
    • Jinsong Zhang
    • Jiansong Wang
    • Ting Luan
    • Yigang Zuo
    • Jian Chen
    • Heng Zhang
    • Zhenni Ye
    • Haifeng Wang
    • Bing Hai
  • View Affiliations

  • Published online on: April 18, 2019     https://doi.org/10.3892/or.2019.7131
  • Pages: 3292-3304
  • Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The ubiquitin‑specific protease 9X (USP9X) is a conserved deubiquitinase that has been investigated in several types of human cancer. However, the clinical significance and the biological roles of USP9X in prostate cancer remain unexplored. In the present study, an investigation into the expression and clinical significance of USP9X in prostate cancer revealed that USP9X expression was downregulated in prostate cancer tissues compared with that in healthy tissues. In addition, decreased USP9X expression was associated with a higher Gleason score and local invasion. Depletion of USP9X in prostate cancer LNCaP and PC‑3 cells by small interfering RNA promoted cell invasion and migration. Furthermore, USP9X depletion upregulated matrix metalloproteinase 9 (MMP9) and the phosphorylation of dynamin‑related protein 1 (DRP1). Notably, a significant increase in phosphorylated extracellular signal‑regulated kinase (ERK), an upstream activator of MMP9 and DRP1, was observed. To investigate whether ERK activation was able to increase MMP9 protein levels and induce DRP1 phosphorylation, an ERK inhibitor was used, demonstrating that ERK‑mediated MMP9 production and change in mitochondrial function was critical for the biological function of USP9X in prostate cancer cells. In conclusion, the present study demonstrated that USP9X is downregulated in prostate cancer and functions as an inhibitor of tumor cell invasion, possibly through the regulation of the ERK signaling pathway.

References

1 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Karantanos T, Corn PG and Thompson TC: Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 32:5501–5511. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, Xia C, Sun K, Yang Z, Li H, et al: Changing cancer survival in China during 2003-15: A pooled analysis of 17 population-based cancer registries. Lancet Glob Health. 6:e555–e567. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Hudson SV, O'Malley DM and Miller SM: Achieving optimal delivery of follow-up care for prostate cancer survivors: Improving patient outcomes. Patient Relat Outcome Meas. 6:75–90. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL, Schiewer MJ, McNair C, Jones JK, Aytes A, et al: DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell. 28:97–113. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Fraile JM, Quesada V, Rodriguez D, Freije JM and López-Otín C: Deubiquitinases in cancer: New functions and therapeutic options. Oncogene. 31:2373–2388. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Salmena L and Pandolfi PP: Changing venues for tumour suppression: Balancing destruction and localization by monoubiquitylation. Nat Rev Cancer. 7:409–413. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Oosterkamp HM, Hijmans EM, Brummelkamp TR, Canisius S, Wessels LF, Zwart W and Bernards R: USP9X downregulation renders breast cancer cells resistant to tamoxifen. Cancer Res. 74:3810–3820. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL, Silverstein KA, Grützmann R, Aust D, Rümmele P, et al: The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature. 486:266–270. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Thanh Nguyen H, Andrejeva D, Gupta R, Choudhary C, Hong X, Eichhorn PJ, Loya AC and Cohen SM: Deubiquitylating enzyme USP9× regulates hippo pathway activity by controlling angiomotin protein turnover. Cell Discov. 2:160012016. View Article : Google Scholar : PubMed/NCBI

11 

Wang Y, Liu Y, Yang B, Cao H, Yang CX, Ouyang W, Zhang SM, Yang GF, Zhou FX, Zhou YF, et al: Elevated expression of USP9X correlates with poor prognosis in human non-small cell lung cancer. J Thorac Dis. 7:672–679. 2015.PubMed/NCBI

12 

Fu X, Xie W, Song X, Wu K, Xiao L, Liu Y and Zhang L: Aberrant expression of deubiquitylating enzyme USP9X predicts poor prognosis in gastric cancer. Clin Res Hepatol Gastroenterol. 41:687–692. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, Scardino PT and Pearson JD: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 277:1445–1451. 1997. View Article : Google Scholar : PubMed/NCBI

15 

Fine SW: Evolution in prostate cancer staging: Pathology updates from AJCC 8th edition and opportunities that remain. Adv Anat Pathol. 25:327–332. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Braunhut BL, Punnen S and Kryvenko ON: Updates on grading and staging of prostate cancer. Surg Pathol Clin. 11:759–774. 2018. View Article : Google Scholar : PubMed/NCBI

17 

Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI

18 

Jia D, Park JH, Jung KH, Levine H and Kaipparettu BA: Elucidating the metabolic plasticity of cancer: Mitochondrial reprogramming and hybrid metabolic states. Cells. 7:doi: 10.3390/cells7030021. 2018. View Article : Google Scholar : PubMed/NCBI

19 

Paupe V and Prudent J: New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochem Biophys Res Commun. 500:75–86. 2018. View Article : Google Scholar : PubMed/NCBI

20 

Zhou C, Wang Y, Peng J, Li C, Liu P and Shen X: SNX10 plays a critical role in MMP9 secretion via JNK-p38-ERK signaling pathway. J Cell Biochem. 118:4664–4671. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Huang CY, Chiang SF, Chen WT, Ke TW, Chen TW, You YS, Lin CY, Chao KSC and Huang CY: HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer. Cell Death Dis. 9:10042018. View Article : Google Scholar : PubMed/NCBI

22 

Wood SA, Pascoe WS, Ru K, Yamada T, Hirchenhain J, Kemler R and Mattick JS: Cloning and expression analysis of a novel mouse gene with sequence similarity to the Drosophila fat facets gene. Mech Dev. 63:29–38. 1997. View Article : Google Scholar : PubMed/NCBI

23 

Toloczko A, Guo F, Yuen HF, Wen Q, Wood SA, Ong YS, Chan PY, Shaik AA, Gunaratne J, Dunne MJ, et al: Deubiquitinating enzyme USP9X suppresses tumor growth via LATS kinase and core components of the hippo pathway. Cancer Res. 77:4921–4933. 2017.PubMed/NCBI

24 

McGarry E, Gaboriau D, Rainey MD, Restuccia U, Bachi A and Santocanale C: The deubiquitinase USP9X maintains DNA replication fork stability and DNA damage checkpoint responses by regulating CLASPIN during S-phase. Cancer Res. 76:2384–2393. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Wu Y, Yu X, Yi X, Wu K, Dwabe S, Atefi M, Elshimali Y, Kemp KT II, Bhat K, Haro J, et al: Aberrant phosphorylation of SMAD4 Thr277-mediated USP9×-SMAD4 interaction by free fatty acids promotes breast cancer metastasis. Cancer Res. 77:1383–1394. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O'Rourke K, Bazan F, Eastham-Anderson J, et al: Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 463:103–107. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Ding X, Yang DR, Xia L, Chen B, Yu S, Niu Y, Wang M, Li G and Chang C: Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating macrophages with alteration of the TIMP-1/MMP2/MMP9 signals. Mol Cancer. 14:162015. View Article : Google Scholar : PubMed/NCBI

28 

Moroz A, Delella FK, Almeida R, Lacorte LM, Fávaro WJ, Deffune E and Felisbino SL: Finasteride inhibits human prostate cancer cell invasion through MMP2 and MMP9 downregulation. PLoS One. 8:e847572013. View Article : Google Scholar : PubMed/NCBI

29 

Kato T, Fujita Y, Nakane K, Kojima T, Nozawa Y, Deguchi T and Ito M: ETS1 promotes chemoresistance and invasion of paclitaxel-resistant, hormone-refractory PC3 prostate cancer cells by up-regulating MDR1 and MMP9 expression. Biochem Biophys Res Commun. 417:966–971. 2012. View Article : Google Scholar : PubMed/NCBI

30 

London CA, Sekhon HS, Arora V, Stein DA, Iversen PL and Devi GR: A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity. Cancer Gene Ther. 10:823–832. 2003. View Article : Google Scholar : PubMed/NCBI

31 

Zhang X, Yao X, Qin C, Luo P and Zhang J: Investigation of the molecular mechanisms underlying metastasis in prostate cancer by gene expression profiling. Exp Ther Med. 12:925–932. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Clarke NW, Hart CA and Brown MD: Molecular mechanisms of metastasis in prostate cancer. Asian J Androl. 11:57–67. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Pollard TD and Cooper JA: Actin, a central player in cell shape and movement. Science. 326:1208–1212. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Westermann B: Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 11:872–884. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW and Tu Y: Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 32:4814–4824. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Pal AD, Basak NP, Banerjee AS and Banerjee S: Epstein-Barr virus latent membrane protein-2A alters mitochondrial dynamics promoting cellular migration mediated by Notch signaling pathway. Carcinogenesis. 35:1592–1601. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Hollenbeck PJ and Saxton WM: The axonal transport of mitochondria. J Cell Sci. 118:5411–5419. 2005. View Article : Google Scholar : PubMed/NCBI

38 

Yin M, Lu Q, Liu X, Wang T, Liu Y and Chen L: Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ROCK1 pathway. Biochem Biophys Res Commun. 478:663–668. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Zhang J, Zhang Y, Wu W, Wang F, Liu X, Shui G and Nie C: Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion. Cell Death Dis. 8:e31512017. View Article : Google Scholar : PubMed/NCBI

40 

Fu L, Dong Q, He J, Wang X, Xing J, Wang E, Qiu X and Li Q: SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene. 36:2724–2736. 2017. View Article : Google Scholar : PubMed/NCBI

41 

Kato T, Fujita Y, Nakane K, Mizutani K, Terazawa R, Ehara H, Kanimoto Y, Kojima T, Nozawa Y, Deguchi T and Ito M: CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling. Cytokine. 64:251–257. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Cai J, Wang J, Huang Y, Wu H, Xia T, Xiao J, Chen X, Li H, Qiu Y, Wang Y, et al: ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death Dis. 7:e24592016. View Article : Google Scholar : PubMed/NCBI

43 

Shen G, Lin Y, Yang X, Zhang J, Xu Z and Jia H: MicroRNA-26b inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting USP9X. BMC Cancer. 14:3932014. View Article : Google Scholar : PubMed/NCBI

44 

Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries CG, Kapur P, Lotan Y, et al: Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci USA. 111:4251–4256. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Zhang C, Cai TY, Zhu H, Yang LQ, Jiang H, Dong XW, Hu YZ, Lin NM, He QJ and Yang B: Synergistic antitumor activity of gemcitabine and ABT-737 in vitro and in vivo through disrupting the interaction of USP9X and Mcl-1. Mol Cancer Ther. 10:1264–1275. 2011. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 41 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhang, J., Wang, J., Luan, T., Zuo, Y., Chen, J., Zhang, H. ... Hai, B. (2019). Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics. Oncology Reports, 41, 3292-3304. https://doi.org/10.3892/or.2019.7131
MLA
Zhang, J., Wang, J., Luan, T., Zuo, Y., Chen, J., Zhang, H., Ye, Z., Wang, H., Hai, B."Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics". Oncology Reports 41.6 (2019): 3292-3304.
Chicago
Zhang, J., Wang, J., Luan, T., Zuo, Y., Chen, J., Zhang, H., Ye, Z., Wang, H., Hai, B."Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics". Oncology Reports 41, no. 6 (2019): 3292-3304. https://doi.org/10.3892/or.2019.7131