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Variants of ubiquitin-specific peptidase 24 play a crucial role in lung cancer malignancy

Oncogene volume 35, pages 3669–3680 (2016)Cite this article

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Abstract

Ubiquitin is a critical modifier regulating the degradation and function of its target proteins during posttranslational modification. Here we found that ubiquitin-specific peptidase 24 (USP24) is highly expressed in cell lines with enhanced malignancy and in late-stage lung cancer clinical samples. Studying single-nucleotide polymorphisms (SNPs) of USP24 using genomic DNA of lung cancer patients revealed an increase in SNP 7656C/T. When using RNA specimens instead of the genomic DNA of lung cancer patients, we found significant increases in the ratios of variants 930C/T and 7656T/C, suggesting that variants at these two sites are not only caused by the SNP of DNA but also by the RNA editing. USP24-930T and USP24-7656C increase USP24 expression levels by increasing RNA stability. Knocking down USP24 increased Suv39h1 level through a decrease in mouse double-minute 2 homolog levels, thus enhancing lysine-9 methylation of histone H3, and resulting in the prevention of lung cancer malignancy. In conclusion, as USP24 variant analysis revealed a higher ratio of variants in blood specimens of lung cancer patients than that in normal individuals, USP24-930T and USP24-7656C might be useful as diagnostic markers for cancer detection.

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References

  1. Heideker J, Wertz IE . DUBs, the regulation of cell identity and disease. Biochem J 2015; 467: 191.

    Article  CAS  Google Scholar 

  2. Garg AV, Ahmed M, Vallejo AN, Ma A, Gaffen SL . The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling. Sci Signal 2013; 6 ra44.

    Article  Google Scholar 

  3. Wang Y, Serricchio M, Jauregui M, Shanbhag R, Stoltz T, Di Paolo CT et al. Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 2015; 11: 595–606.

    Article  CAS  Google Scholar 

  4. Zhao GY, Lin ZW, Lu CL, Gu J, Yuan YF, Xu FK et al. USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma. Tumour Biol 2015; 36: 1721–1729.

    Article  CAS  Google Scholar 

  5. Li Y, Schrodi S, Rowland C, Tacey K, Catanese J, Grupe A . Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease. Hum Mutat 2006; 27: 1017–1023.

    Article  CAS  Google Scholar 

  6. Wu YR, Chen CM, Chen YC, Chao CY, Ro LS, Fung HC et al. Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese. Clin Chim Acta 2010; 411: 955–958.

    Article  CAS  Google Scholar 

  7. Zhao B, Song W, Chen YP, Huang R, Chen K, Cao B et al. Association analysis of single-nucleotide polymorphisms of USP24 and USP40 with Parkinson's disease in the Han Chinese population. Eur Neurol 2012; 68: 181–184.

    Article  CAS  Google Scholar 

  8. Chiba T, Saito T, Yuki K, Zen Y, Koide S, Kanogawa N et al. Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma. Int J Cancer 2015; 136: 289–298.

    Article  CAS  Google Scholar 

  9. Wu PC, Lu JW, Yang JY, Lin IH, Ou DL, Lin YH et al. H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis. Cancer Res 2014; 74: 7333–7343.

    Article  CAS  Google Scholar 

  10. Khanal P, Kim G, Lim SC, Yun HJ, Lee KY, Choi HK et al. Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer. FASEB J 2013; 27: 4606–4618.

    Article  CAS  Google Scholar 

  11. Bosch-Presegue L, Raurell-Vila H, Marazuela-Duque A, Kane-Goldsmith N, Valle A, Oliver J et al. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell 2011; 42: 210–223.

    Article  CAS  Google Scholar 

  12. Rebbani K, Marchio A, Ezzikouri S, Afifi R, Kandil M, Bahri O et al. TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma. Mol Cancer 2015; 14: 74.

    Article  Google Scholar 

  13. Blanc V, Davidson NO . APOBEC-1-mediated RNA editing. Wiley Interdiscip Rev Syst Biol Med 2010; 2: 594–602.

    Article  CAS  Google Scholar 

  14. Torres AG, Pineyro D, Filonava L, Stracker TH, Batlle E, Ribas de Pouplana L . A-to-I editing on tRNAs: biochemical, biological and evolutionary implications. FEBS Lett 2014; 588: 4279–4286.

    Article  CAS  Google Scholar 

  15. Guo W, Grewe F, Mower JP . Variable frequency of plastid RNA editing among ferns and repeated loss of uridine-to-cytidine editing from vascular plants. PLoS One 2015; 10: e0117075.

    Article  Google Scholar 

  16. Villegas J, Muller I, Arredondo J, Pinto R, Burzio LO . A putative RNA editing from U to C in a mouse mitochondrial transcript. Nucleic Acids Res 2002; 30: 1895–1901.

    Article  CAS  Google Scholar 

  17. Blons H, Pallier K, Le Corre D, Danel C, Tremblay-Gravel M, Houdayer C et al. Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma. BMC Med Genomics 2008; 1: 25.

    Article  Google Scholar 

  18. Liu C, Rennie WA, Carmack CS, Kanoria S, Cheng J, Lu J et al. Effects of genetic variations on microRNA: target interactions. Nucleic Acids Res 2014; 42: 9543–9552.

    Article  CAS  Google Scholar 

  19. Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res 2010; 70: 2789–2798.

    Article  CAS  Google Scholar 

  20. Whibley C, Pharoah PD, Hollstein M . p53 polymorphisms: cancer implications. Nat Rev Cancer 2009; 9: 95–107.

    Article  CAS  Google Scholar 

  21. Kramer K, Thye T, Treszl A, Peine S, Koch M, Sterneck M et al. Polymorphism in NFKBIA gene is associated with recurrent acute rejections in liver transplant recipients. Tissue Antigens 2014; 84: 370–377.

    Article  CAS  Google Scholar 

  22. Schmid F, Burock S, Klockmeier K, Schlag PM, Stein U . SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer. Mol Cancer 2012; 11: 49.

    Article  CAS  Google Scholar 

  23. Vage J, Lingaas F . Single nucleotide polymorphisms (SNPs) in coding regions of canine dopamine- and serotonin-related genes. BMC Genet 2008; 9: 10.

    Article  Google Scholar 

  24. Tomaselli S, Locatelli F, Gallo A . The RNA editing enzymes ADARs: mechanism of action and human disease. Cell Tissue Res 2014; 356: 527–532.

    Article  CAS  Google Scholar 

  25. Sharma S, Patnaik SK, Taggart RT, Kannisto ED, Enriquez SM, Gollnick P et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat Commun 2015; 6: 6881.

    Article  CAS  Google Scholar 

  26. Avesson L, Barry G . The emerging role of RNA and DNA editing in cancer. Biochim Biophys Acta 2014; 1845: 308–316.

    CAS  PubMed  Google Scholar 

  27. Dominissini D, Moshitch-Moshkovitz S, Amariglio N, Rechavi G . Adenosine-to-inosine RNA editing meets cancer. Carcinogenesis 2011; 32: 1569–1577.

    Article  CAS  Google Scholar 

  28. Zhang L, Lubin A, Chen H, Sun Z, Gong F . The deubiquitinating protein USP24 interacts with DDB2 and regulates DDB2 stability. Cell Cycle 2012; 11: 4378–4384.

    Article  CAS  Google Scholar 

  29. Zhang L, Nemzow L, Chen H, Lubin A, Rong X, Sun Z et al. The deubiquitinating enzyme USP24 is a regulator of the UV damage response. Cell Rep 2015; 10: 140–147.

    Article  CAS  Google Scholar 

  30. Ranaweera RS, Yang X . Auto-ubiquitination of Mdm2 enhances its substrate ubiquitin ligase activity. J Biol Chem 2013; 288: 18939–18946.

    Article  CAS  Google Scholar 

  31. Xu C, Fan CD, Wang X . Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase. Oncogene 2015; 34: 281–289.

    Article  CAS  Google Scholar 

  32. Zou Q, Jin J, Hu H, Li HS, Romano S, Xiao Y et al. USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 2014; 15: 562–570.

    Article  CAS  Google Scholar 

  33. Honda R, Tanaka H, Yasuda H . Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420: 25–27.

    Article  CAS  Google Scholar 

  34. Shi D, Gu W . Dual roles of MDM2 in the regulation of p53: ubiquitination dependent and ubiquitination independent mechanisms of MDM2 repression of p53 activity. Genes Cancer 2012; 3: 240–248.

    Article  CAS  Google Scholar 

  35. Yang Y, Liu R, Qiu R, Zheng Y, Huang W, Hu H et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene 2015; 34: 104–118.

    Article  Google Scholar 

  36. Nagahara A, Nakayama M, Oka D, Tsuchiya M, Kawashima A, Mukai M et al. SERPINE2 is a possible candidate promotor for lymph node metastasis in testicular cancer. Biochem Biophyscal Res Commun 2010; 391: 1641–1646.

    Article  CAS  Google Scholar 

  37. Katono K, Sato Y, Jiang SX, Kobayashi M, Nagashio R, Ryuge S et al. Prognostic significance of MYH9 expression in resected non-small cell lung cancer. PLoS One 2015; 10: e0121460.

    Article  Google Scholar 

  38. Strock CJ, Park JI, Nakakura EK, Bova GS, Isaacs JT, Ball DW et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res 2006; 66: 7509–7515.

    Article  CAS  Google Scholar 

  39. Dong C, Wu Y, Wang Y, Wang C, Kang T, Rychahou PG et al. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 2013; 32: 1351–1362.

    Article  CAS  Google Scholar 

  40. Das TK, Dana D, Paroly SS, Perumal SK, Singh S, Jhun H et al. Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis. Oncogenesis 2013; 2: e69.

    Article  CAS  Google Scholar 

  41. Li S, Wang L, Zhao Q, Liu Y, He L, Xu Q et al. SHP2 positively regulates TGFbeta1-induced epithelial-mesenchymal transition modulated by its novel interacting protein Hook1. J Biol Chem 2014; 289: 34152–34160.

    Article  CAS  Google Scholar 

  42. Yanagisawa T, Kiribuchi-Otobe C, Hirano H, Suzuki Y, Fujita M . Detection of single nucleotide polymorphism (SNP) controlling the waxy character in wheat by using a derived cleaved amplified polymorphic sequence (dCAPS) marker. Theor Appl Genet 2003; 107: 84–88.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Cheng Kung University project of the Program for Promoting Academic Excellence and Developing World Class Research Centers, together with grants MOST 103-2320-B-006-035-MY3 and MOST 103-2321-B-006-023-MY3 obtained from the Ministry of Science and Technology, Taiwan. In addition, we thank the Taiwan Lung Cancer Tissue/Specimen and Information Resource Center at National Health Research Institute (NHRI), Taiwan for blood samples’ support. This Center was supported by grants from National Research Program for Biopharmaceuticals of National Science Council, Taiwan.

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Author notes

  1. Y-C Wang and S-A Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

    Y-C Wang & J-J Hung

  2. Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan

    S-A Wang, T-I Hsu, W-B Yang & J-J Hung

  3. Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan

    P-H Chen & Y-P Chuang

  4. Center for Infectious Disease and Signal Transduction, National Cheng Kung University, Tainan, Taiwan

    T-I Hsu & J-J Hung

  5. The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan

    T-I Hsu

  6. Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan

    W-C Su

  7. Department of Life Science, College of Bioscience in Biotechnology, National Cheng Kung University, Tainan, Taiwan

    H-J Liaw

  8. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

    W-C Chang & J-J Hung

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Correspondence to J-J Hung.

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Wang, YC., Wang, SA., Chen, PH. et al. Variants of ubiquitin-specific peptidase 24 play a crucial role in lung cancer malignancy. Oncogene 35, 3669–3680 (2016). https://doi.org/10.1038/onc.2015.432

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