Epstein-Barr Virus Down-Regulates Tumor Suppressor Expression

English version České info

Many oncogenic viruses exhibit cellular transforming properties, often involving oncogenes activation and tumor suppressor genes inactivation. The DOK1 gene is a newly identified tumor suppressor gene with altered expression via hypermethylation of its promoter in a variety of human cancers, including head and neck, lung, gastric and others. In addition, a correlation has been reported between DOK1 aberrant hypermethylation and the presence of oncogenic viruses such as hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) and Epstein-Barr virus (EBV) in Burkitt's lymphoma-derived cell lines. Here we demonstrate for the first time that EBV is directly involved in the inhibition of DOK1 expression in B-cells. We show that EBV leads to epigenetic repression of DOK1 through increased DNA methylation of its promoter and H3K27 tri-methylation. The LMP1 oncoprotein plays a key role in the repression of DOK1 expression. It promotes the formation and the recruitment to the DOK1 promoter of transcriptionally inhibitory complexes composed of E2F1/pRB/DNMT1 and of EZH2 which is part of the polycomb repressive complex 2. Interestingly, one or more additional EBV protein(s) cooperate(s) with LMP1 in inducing massive DNA methylation at the DOK1 promoter, leading to the loss of E2F1 complexes recruitment and even stronger repression of DOK1 expression.

Vyšlo v časopise: Epstein-Barr Virus Down-Regulates Tumor Suppressor Expression. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004125
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004125

Souhrn

Zdroje

1. MashimaR, HishidaY, TezukaT, YamanashiY (2009) The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev 232: 273–285.

2. Di CristofanoA, NikiM, ZhaoM, KarnellFG, ClarksonB, et al. (2001) p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl). J Exp Med 194: 275–284.

3. BergerAH, NikiM, MorottiA, TaylorBS, SocciND, et al. (2010) Identification of DOK genes as lung tumor suppressors. Nature Genetics 42: 216–U227.

4. YasudaT, ShirakataM, IwamaA, IshiiA, EbiharaY, et al. (2004) Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. J Exp Med 200: 1681–1687.

5. YasudaT, BundoK, HinoA, HondaK, InoueA, et al. (2007) Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. Int Immunol 19: 487–495.

6. NelmsK, SnowAJ, Noben-TrauthK (1998) Dok1 encoding p62(dok) maps to mouse chromosome 6 and human chromosome 2 in a region of translocation in chronic lymphocytic leukemia. Genomics 53: 243–245.

7. JanasJA, Van AelstL (2011) Oncogenic tyrosine kinases target Dok-1 for ubiquitin-mediated proteasomal degradation to promote cell transformation. Mol Cell Biol 31: 2552–2565.

8. LeeS, RoyF, GalmariniCM, AccardiR, MichelonJ, et al. (2004) Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia. Oncogene 23: 2287–2297.

9. SaulnierA, VaissiereT, YueJ, SioudaM, MalfroyM, et al. (2012) Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers. Int J Cancer 130: 2484–2494.

10. LambertMP, PaliwalA, VaissiereT, CheminI, ZoulimF, et al. (2011) Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J Hepatol 54: 705–715.

11. BalassianoK, LimaS, JenabM, OvervadK, TjonnelandA, et al. (2011) Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Cancer Lett 311: 85–95.

12. YoungLS, RickinsonAB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4: 757–768.

13. StrausSE (1988) The chronic mononucleosis syndrome. J Infect Dis 157: 405–412.

14. EpsteinMA, AchongBG, BarrYM (1964) Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma. Lancet 1: 702–703.

15. FlavellKJ, MurrayPG (2000) Hodgkin's disease and the Epstein-Barr virus. Mol Pathol 53: 262–269.

16. CarboneA, GloghiniA, DottiG (2008) EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist 13: 577–585.

17. MatsusakaK, KanedaA, NagaeG, UshikuT, KikuchiY, et al. (2011) Classification of Epstein-Barr virus-positive gastric cancers by definition of DNA methylation epigenotypes. Cancer Res 71: 7187–7197.

18. FarrellPJ (1995) Epstein-Barr virus immortalizing genes. Trends Microbiol 3: 105–109.

19. BornkammGW, HammerschmidtW (2001) Molecular virology of Epstein-Barr virus. Philos Trans R Soc Lond B Biol Sci 356: 437–459.

20. KayeKM, IzumiKM, KieffE (1993) Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A 90: 9150–9154.

21. Cahir McFarlandED, IzumiKM, MosialosG (1999) Epstein-barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 18: 6959–6964.

22. EliopoulosAG, YoungLS (2001) LMP1 structure and signal transduction. Semin Cancer Biol 11: 435–444.

23. MosialosG, BirkenbachM, YalamanchiliR, VanArsdaleT, WareC, et al. (1995) The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389–399.

24. RobertsML, CooperNR (1998) Activation of a ras-MAPK-dependent pathway by Epstein-Barr virus latent membrane protein 1 is essential for cellular transformation. Virology 240: 93–99.

25. EliopoulosAG, GallagherNJ, BlakeSM, DawsonCW, YoungLS (1999) Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J Biol Chem 274: 16085–16096.

26. HuenDS, HendersonSA, Croom-CarterD, RoweM (1995) The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene 10: 549–560.

27. EliopoulosAG, BlakeSM, FloettmannJE, RoweM, YoungLS (1999) Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. J Virol 73: 1023–1035.

28. DawsonCW, PortRJ, YoungLS (2012) The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol 22: 144–153.

29. SioudaM, YueJ, ShuklaR, GuillermierS, HercegZ, et al. (2012) Transcriptional regulation of the human tumor suppressor DOK1 by E2F1. Mol Cell Biol 32: 4877–4890.

30. DevergneO, HatzivassiliouE, IzumiKM, KayeKM, KleijnenMF, et al. (1996) Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol 16: 7098–7108.

31. IzumiKM, KieffED (1997) The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci U S A 94: 12592–12597.

32. AtkinsonPG, CoopeHJ, RoweM, LeySC (2003) Latent membrane protein 1 of Epstein-Barr virus stimulates processing of NF-kappa B2 p100 to p52. J Biol Chem 278: 51134–51142.

33. NikiM, Di CristofanoA, ZhaoM, HondaH, HiraiH, et al. (2004) Role of Dok-1 and Dok-2 in leukemia suppression. J Exp Med 200: 1689–1695.

34. LeeS, HuangH, NiuY, TommasinoM, LenoirG, et al. (2007) Dok1 expression and mutation in Burkitt's lymphoma cell lines. Cancer Lett 245: 44–50.

35. PaschosK, SmithP, AndertonE, MiddeldorpJM, WhiteRE, et al. (2009) Epstein-barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim. PLoS Pathog 5: e1000492.

36. HinoR, UozakiH, MurakamiN, UshikuT, ShinozakiA, et al. (2009) Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res 69: 2766–2774.

37. SakumaK, ChongJM, SudoM, UshikuT, InoueY, et al. (2004) High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma. Int J Cancer 112: 273–278.

38. PaschosK, AlldayMJ (2010) Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol 18: 439–447.

39. UristM, TanakaT, PoyurovskyMV, PrivesC (2004) p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev 18: 3041–3054.

40. ZhangHJ, LiWJ, YangSY, LiSY, NiJH, et al. (2009) 8-Chloro-adenosine-induced E2F1 promotes p14ARF gene activation in H1299 cells through displacing Sp1 from multiple overlapping E2F1/Sp1 sites. J Cell Biochem 106: 464–472.

41. AccardiRFI, GruffatH, MariggiòG, Le Calvez-KelmF, VoegeleC, BartoschB, Hernandez-VargasH, McKayJ, SyllaBS, ManetE, TommasinoM (2013 Mar) Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ΔNp73α. PLoS Pathog 9(3).

42. LeeS, AndrieuC, SaltelF, DestaingO, AuclairJ, et al. (2004) IkappaB kinase beta phosphorylates Dok1 serines in response to TNF, IL-1, or gamma radiation. Proc Natl Acad Sci U S A 101: 17416–17421.

43. DelecluseHJ, HilsendegenT, PichD, ZeidlerR, HammerschmidtW (1998) Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A 95: 8245–8250.

44. DelecluseHJ, PichD, HilsendegenT, BaumC, HammerschmidtW (1999) A first-generation packaging cell line for Epstein-Barr virus-derived vectors. Proc Natl Acad Sci U S A 96: 5188–5193.

45. DirmeierU, NeuhierlB, KilgerE, ReisbachG, SandbergML, et al. (2003) Latent membrane protein 1 is critical for efficient growth transformation of human B cells by Epstein-Barr virus. Cancer Research 63: 2982–2989.

46. FrommerM, McDonaldLE, MillarDS, CollisCM, WattF, et al. (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89: 1827–1831.