Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi’s sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe. 2014;15:266–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:1865–9.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332:1186–91.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123:187–94.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Bonnet F, Lewden C, May T, Heripret L, Jougla E, Bevilacqua S, et al. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer. 2004;101:317–24.

    Article  PubMed  Google Scholar 

  6. 6.

    Labo N, Miley W, Benson CA, Campbell TB, Whitby D. Epidemiology of Kaposi’s sarcoma-associated herpesvirus in HIV-1-infected US persons in the era of combination antiretroviral therapy. AIDS. 2015;29:1217–25.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Jenkins FJ, Hoffman LJ, Liegey-Dougall A. Reactivation of and primary infection with human herpesvirus 8 among solid-organ transplant recipients. J Infect Dis. 2002;185:1238–43.

    Article  PubMed  Google Scholar 

  8. 8.

    Luppi M, Barozzi P, Santagostino G, Trovato R, Schulz TF, Marasca R, et al. Molecular evidence of organ-related transmission of Kaposi sarcoma-associated herpesvirus or human herpesvirus-8 in transplant patients. Blood. 2000;96:3279–81.

    PubMed  CAS  Google Scholar 

  9. 9.

    Ariza-Heredia EJ, Razonable RR. Human herpes virus 8 in solid organ transplantation. Transplantation. 2011;92:837–44.

    Article  PubMed  Google Scholar 

  10. 10.

    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Hughes JF, Coffin JM. Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution. Nat Genet. 2001;29:487–9.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Dewannieux M, Harper F, Richaud A, Letzelter C, Ribet D, Pierron G, et al. Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. 2006;16:1548–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Lee YN, Bieniasz PD. Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog. 2007;3:e10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Kraus B, Boller K, Reuter A, Schnierle BS. Characterization of the human endogenous retrovirus K Gag protein: identification of protease cleavage sites. Retrovirology. 2011;8:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Depil S, Roche C, Dussart P, Prin L. Expression of a human endogenous retrovirus, HERV-K, in the blood cells of leukemia patients. Leukemia. 2002;16:254–9.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Contreras-Galindo R, Kaplan MH, Leissner P, Verjat T, Ferlenghi I, Bagnoli F, et al. Human endogenous retrovirus K (HML-2) elements in the plasma of people with lymphoma and breast cancer. J Virol. 2008;82:9329–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin B, Frerich K, et al. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst. 2012;104:189–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    Armbruester V, Sauter M, Krautkraemer E, Meese E, Kleiman A, Best B, et al. A novel gene from the human endogenous retrovirus K expressed in transformed cells. Clin Cancer Res. 2002;8:1800–7.

    PubMed  CAS  Google Scholar 

  19. 19.

    Buscher K, Trefzer U, Hofmann M, Sterry W, Kurth R, Denner J. Expression of human endogenous retrovirus K in melanomas and melanoma cell lines. Cancer Res. 2005;65:4172–80.

    Article  PubMed  Google Scholar 

  20. 20.

    Sutkowski N, Conrad B, Thorley-Lawson DA, Huber BT. Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity. 2001;15:579–89.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Sutkowski N, Chen G, Calderon G, Huber BT. Epstein-Barr virus latent membrane protein LMP-2A is sufficient for transactivation of the human endogenous retrovirus HERV-K18 superantigen. J Virol. 2004;78:7852–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Hsiao FC, Lin M, Tai A, Chen G, Huber BT. Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. J Immunol. 2006;177:2056–60.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Mbisa GL, Miley W, Gamache CJ, Gillette WK, Esposito D, Hopkins R, et al. Detection of antibodies to Kaposi’s sarcoma-associated herpesvirus: a new approach using K8.1 ELISA and a newly developed recombinant LANA ELISA. J Immunol Methods. 2010;356:39–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Benavente Y, Mbisa G, Labo N, Casabonne D, Becker N, Maynadie M, et al. Antibodies against lytic and latent Kaposi’s sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study. Br J Cancer. 2011;105:1768–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10:707–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Ye F, Lei X, Gao SJ. Mechanisms of Kaposias sarcoma-associated herpesvirus latency and reactivation. Adv Virol. 2011;2011:193860

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kellam P, Boshoff C, Whitby D, Matthews S, Weiss RA, Talbot SJ. Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome. J Hum Virol. 1997;1:19–29.

    PubMed  CAS  Google Scholar 

  28. 28.

    Grossmann C, Podgrabinska S, Skobe M, Ganem D. Activation of NF-kappaB by the latent vFLIP gene of Kaposi’s sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype. J Virol. 2006;80:7179–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    Qin Z, Dai L, Slomiany MG, Toole BP, Parsons C. Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus. Cancer Res. 2010;70:3884–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem. 2002;277:13745–51.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi’s sarcoma-associated herpesvirus. Proc Natl Acad Sci USA. 1998;95:10866–71.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Dai L, Chen Y, Toole B, Parsons C, Qin Z. Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients. Cancer Lett. 2015;362:158–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Manghera M, Douville RN. Endogenous retrovirus-K promoter: a landing strip for inflammatory transcription factors? Retrovirology. 2013;10:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Fuchs NV, Kraft M, Tondera C, Hanschmann KM, Lower J, Lower R. Expression of the human endogenous retrovirus (HERV) group HML-2/HERV-K does not depend on canonical promoter elements but is regulated by transcription factors Sp1 and Sp3. J Virol. 2011;85:3436–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Kim JD, Yu S, Kim J. YY1 is autoregulated through its own DNA-binding sites. BMC Mol Biol. 2009;10:85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Verma SC, Borah S, Robertson ES. Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus up-regulates transcription of human telomerase reverse transcriptase promoter through interaction with transcription factor Sp1. J Virol. 2004;78:10348–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Qian LW, Xie J, Ye F, Gao SJ. Kaposi’s sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases. J Virol. 2007;81:7001–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Lower R, Tonjes RR, Korbmacher C, Kurth R, Lower J. Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K. J Virol. 1995;69:141–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Magin C, Lower R, Lower J. cORF and RcRE, the Rev/Rex and RRE/RxRE homologues of the human endogenous retrovirus family HTDV/HERV-K. J Virol. 1999;73:9496–507.

    PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Buscher K, Hahn S, Hofmann M, Trefzer U, Ozel M, Sterry W, et al. Expression of the human endogenous retrovirus-K transmembrane envelope, Rec and Np9 proteins in melanomas and melanoma cell lines. Melanoma Res. 2006;16:223–34.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Chen T, Meng Z, Gan Y, Wang X, Xu F, Gu Y, et al. The viral oncogene Np9 acts as a critical molecular switch for co-activating beta-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia. 2013;27:1469–78.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Gonzalez-Hernandez MJ, Swanson MD, Contreras-Galindo R, Cookinham S, King SR, Noel RJ Jr, et al. Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1. J Virol. 2012;86:7790–805.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Gross H, Barth S, Pfuhl T, Willnecker V, Spurk A, Gurtsevitch V, et al. The NP9 protein encoded by the human endogenous retrovirus HERV-K(HML-2) negatively regulates gene activation of the Epstein-Barr virus nuclear antigen 2 (EBNA2). Int J Cancer. 2011;129:1105–15.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Tang W, Chang SB, Hemler ME. Links between CD147 function, glycosylation, and caveolin-1. Mol Biol Cell. 2004;15:4043–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. 45.

    Dai L, Qiao J, Nguyen D, Struckhoff AP, Doyle L, Bonstaff K, et al. Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi’s sarcoma-associated herpesvirus. Oncotarget. 2016;7:10459–71.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    An FQ, Folarin HM, Compitello N, Roth J, Gerson SL, McCrae KR, et al. Long-term-infected telomerase-immortalized endothelial cells: a model for Kaposi’s sarcoma-associated herpesvirus latency in vitro and in vivo. J Virol. 2006;80:4833–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Maksakova IA, Mager DL, Reiss D. Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell Mol Life Sci. 2008;65:3329–47.

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    He M, Zhang W, Bakken T, Schutten M, Toth Z, Jung JU, et al. Cancer angiogenesis induced by Kaposi sarcoma-associated herpesvirus is mediated by EZH2. Cancer Res. 2012;72:3582–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Kim KY, Huerta SB, Izumiya C, Wang DH, Martinez A, Shevchenko B, et al. Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A. J Virol. 2013;87:6782–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Di Bartolo DL, Cannon M, Liu YF, Renne R, Chadburn A, Boshoff C, et al. KSHV LANA inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta type II receptor. Blood. 2008;111:4731–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. 51.

    Shamay M, Krithivas A, Zhang J, Hayward SD. Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi’s sarcoma-associated herpesvirus LANA. Proc Natl Acad Sci USA. 2006;103:14554–9.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Li Z, Sheng T, Wan X, Liu T, Wu H, Dong J. Expression of HERV-K correlates with status of MEK-ERK and p16INK4A-CDK4 pathways in melanoma cells. Cancer Invest. 2010;28:1031–7.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Friborg J Jr., Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature. 1999;402:889–94.

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    An FQ, Compitello N, Horwitz E, Sramkoski M, Knudsen ES, Renne R. The latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest. J Biol Chem. 2005;280:3862–74.

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Hohn O, Hanke K, Bannert N. HERV-K(HML-2), the best preserved family of HERVs: endogenization, expression, and implications in health and disease. Front Oncol. 2013;3:246.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Downey RF, Sullivan FJ, Wang-Johanning F, Ambs S, Giles FJ, Glynn SA. Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice? Int J Cancer. 2015;137:1249–57.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Wong JP, Damania B. Modulation of oncogenic signaling networks by Kaposi’s sarcoma-associated herpesvirus. Biol Chem. 2017;398:911–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. 58.

    Li W, Jia X, Shen C, Zhang M, Xu J, Shang Y, et al. A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget. 2016;7:32286–305.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Li S, Hu H, He Z, Liang D, Sun R, Lan K. Fine-tuning of the Kaposi’s sarcoma-associated herpesvirus life cycle in neighboring cells through the RTA-JAG1-Notch pathway. PLoS Pathog. 2016;12:e1005900.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    Angelova M, Ferris M, Swan KF, McFerrin HE, Pridjian G, Morris CA, et al. Kaposi’s sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/beta-catenin signaling pathway. Virol J. 2014;11:218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. 61.

    Landen CN Jr., Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G, et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 2005;65:6910–8.

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Gonzalez-Cao M, Iduma P, Karachaliou N, Santarpia M, Blanco J, Rosell R. Human endogenous retroviruses and cancer. Cancer Biol Med. 2016;13:483–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. 63.

    Mangeney M, Heidmann T. Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci USA. 1998;95:14920–5.

    Article  PubMed  CAS  Google Scholar 

  64. 64.

    Dai L, Trillo-Tinoco J, Cao Y, Bonstaff K, Doyle L, Del Valle L, et al. Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood. 2015;126:2821–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. 65.

    Qin Z, Freitas E, Sullivan R, Mohan S, Bacelieri R, Branch D, et al. Upregulation of xCT by KSHV-encoded microRNAs facilitates KSHV dissemination and persistence in an environment of oxidative stress. PLoS Pathog. 2010;6:e1000742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. 66.

    Qin Z, Dai L, Defee M, Findlay VJ, Watson DK, Toole BP, et al. Kaposi’s sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. J Virol. 2013;87:621–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Dai L, Bratoeva M, Toole BP, Qin Z, Parsons C. KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer. 2012;131:834–43.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Rolf Renne at the University of Florida for his kind gifts of TIVE-LTC and TIVE cells and Dr. Friedrich A. Grasser from Universitatsklinikum des Saarlandes, Germany for kindly providing HERV-K NP9 plasmids and antibody. This work was supported by grants from a DOD Career Development Award to (CA140437 to ZQ); a Louisiana Clinical and Translational Science Center Pilot grant (U54GM104940 from NIH), a LSU LIFT2 funding, and NIH P20-GM121288-01 (PI: Krzysztof Reiss) subproject to ZQ; NIH RO1-AI101046, R01-AI106676, and P01CA214091 and Department of Defense W81XWH-16-1-0318 to EKF; the federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E to DW; and the awards from the National Natural Science Foundation of China (81472547, 81672924 to ZQ and 81400164, 81772930 to LD). Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors contribution

LD and ZQ designed and performed experiments, analyzed results, and wrote the manuscript. LDV and WM performed experiments. DW, ACO, and EKF performed statistical analysis and provided critical input.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Zhiqiang Qin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dai, L., Del Valle, L., Miley, W. et al. Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development. Oncogene 37, 4534–4545 (2018). https://doi.org/10.1038/s41388-018-0282-4

Download citation

Further reading

Search