Date Published: June 21, 2019
Publisher: Public Library of Science
Author(s): Fengchao Lang, Rajnish Kumar Singh, Yonggang Pei, Shengwei Zhang, Kunfeng Sun, Erle S. Robertson, Benjamin E. Gewurz.
Epstein–Barr virus (EBV) is a ubiquitous oncogenic virus that induces many cancers. N6-Methyladenosine (m6A) modification regulates many cellular processes. We explored the role of m6A in EBV gene regulation and associated cancers. We have comprehensively defined m6A modification of EBV latent and lytic transcripts. Furthermore, m6A modification demonstrated a functional role in regulation of the stability of viral transcripts. The methyltransferase METTL14 was induced at the transcript and protein levels, and knock-down of METTL14 led to decreased expression of latent EBV transcripts. METTL14 was also significantly induced in EBV-positive tumors, promoted growth of EBV-transformed cells and tumors in Xenograft animal models. Mechanistically, the viral-encoded latent oncoprotein EBNA3C activated transcription of METTL14, and directly interacted with METTL14 to promote its stability. This demonstrated that EBV hijacks METTL14 to drive EBV-mediated tumorigenesis. METTL14 is now a new target for development of therapeutics for treatment of EBV-associated cancers.
Epstein-Barr virus (EBV or HHV4), was the first human oncogenic virus discovered and isolated from a Burkitt’s lymphoma patient in 1964 . EBV contributes to approximately 2% of all cancers . EBV exhibits two distinct phases, lytic infection and latent infection. Latent infection is referred to as latency 0, I, II and III . Viral protein expression during latency III can potently promote indefinite proliferation of primary B-cells ultimately mediating immortalization of infected cells .
Modification of RNA by m6A functions extensively in cellular processes linked to RNA metabolism. These include mRNA stability, translation, splicing and RNA transport . This modification is also involved in the self-renewal of cancer stem cells, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy . Recent studies have provided clues as to understanding the roles of m6A modification during virus infection, however, the function of m6A modification in tumor virus-mediated oncogenesis is completely unknown and not previously explored. We have now mapped the m6A modification of viral transcripts during latent and lytic infection of EBV. We showed that m6A modification can play a major role in promoting latent gene expression and also repression of lytic gene expression. We also show that the level of methyltransferase METTL14 was up-regulated by the essential EBV latent antigen EBNA3C. Furthermore, EBNA3C promoted cell growth and proliferation by co-operating with METTL14. We now establish a novel link between regulation of the EBV epitranscriptome and EBV-mediated oncogenesis (Fig 6N).