Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 9 (11)

Therapeutic Strategies Against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors

Affiliations
Review

Therapeutic Strategies Against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors

Kwai Fung Hui et al. Viruses.

Abstract

Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers.

Keywords: Epstein-Barr virus; Epstein-Barr virus nuclear antigen (EBNA)-3C; apoptosis; cell cycle; lytic reactivation; proteasome inhibitor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of exploitation of ubiquitin-proteasome system by gamma-herpesviruses and the development of cancer hallmarks. (a) Immunological evasion: GAr domain of Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 or Kaposi’s sarcoma-associated herpesvirus (KSHV) central repeat (CR)1 of latency-associated nuclear antigen (LANA)inhibits proteasome so as to prevent the proteolysis of EBNA-1 and the production of its antigenic peptides for major histocompatibility complex (MHC) class I presentation. BDLF3 promotes internalization and proteasomal degradation of MHC molecules. As a result, cytotoxic T lymphocytes (CTLs) are not able to detect and kill the latent viruses-infected cells. Replication and transcription activator (RTA) (KSHV) itself or through stabilization of RTA-associated ubiquitin ligase (RAUL) facilitates the ubiquitination and proteasomal degradation of interferon regulatory factor (IRF)3 and IRF7, which are important for innate immunity; (b) Deregulation of cell cycle: EBNA-3C can stably interact with pRb and recruit SKP1-Cul1-F-box protein (SCF)Skp2 E3-ubiquitin ligase to promote degradation of pRb. Thus, E2F is released and activates the transcription of cyclin-dependent kinases for cell cycle progression. Moreover, EBNA-3C also physically interacts with and degrades Bcl-6 through ubiquitin-specific protease (UPS) but the ligase that facilitates the ubiquitination is still under investigation. EBNA-3C interacts with Pim-1 which enhances the phosphorylation of p21WAF1 and promotes proteasomal degradation of p21WAF1. The association of SCFSkp2 with EBNA-3C or cyclin-dependent kinase (CDK)4/6 with K/V cyclin (KSHV) increases phosphorylation and proteasomal degradation of p27KIP1. Additionally, stabilization of cyclin A by EBNA-3C also promotes degradation of p27KIP1 through UPS. In summary, gamma-herpesviruses possess multiple mechanisms to assist the infected cells to bypass cell cycle checkpoints for proliferation; (c) Inhibition of apoptosis: EBNA-1 displaces p53 in the interaction with ubiquitin-specific protease 7 (USP7), resulting in destabilization of p53 and its degradation by proteasome. On the other hand, MDM2 E3-ubiquitin ligase is recruited and stabilized by EBNA-3C or vIRF4 (KSHV), leading to ubiquitination and proteasomal degradation of p53. Viral interferon regulatory factor (vIRF)4 also inhibits the phosphorylation of p53 by ataxia-telangiectasia mutated (ATM) kinase upon DNA damage response, causing destabilization and proteasomal degradation of p53.

Similar articles

See all similar articles

Cited by 5 PubMed Central articles

References

    1. Blanchette P., Branton P.E. Manipulation of the ubiquitin-proteasome pathway by small DNA tumor viruses. Virology. 2009;384:317–323. doi: 10.1016/j.virol.2008.10.005. - DOI - PubMed
    1. Ding F., Xiao H., Wang M., Xie X., Hu F. The role of the ubiquitin-proteasome pathway in cancer development and treatment. Front. Biosci. 2014;19:886–895. doi: 10.2741/4254. - DOI - PubMed
    1. Honda R., Tanaka H., Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25–27. doi: 10.1016/S0014-5793(97)01480-4. - DOI - PubMed
    1. Knight J.S., Sharma N., Robertson E.S. Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase. Proc. Natl. Acad. Sci. USA. 2005;102:18562–18566. doi: 10.1073/pnas.0503886102. - DOI - PMC - PubMed
    1. Iwahori S., Murata T., Kudoh A., Sato Y., Nakayama S., Isomura H., Kanda T., Tsurumi T. Phosphorylation of P27KIP1 by Epstein-Barr virus protein kinase induces its degradation through SCFSKP2 ubiquitin ligase actions during viral lytic replication. J. Biol. Chem. 2009;284:18923–18931. doi: 10.1074/jbc.M109.015123. - DOI - PMC - PubMed

MeSH terms

Substances

Feedback