Oncogenic Epstein–Barr virus recruits Nm23-H1 to regulate chromatin modifiers

Abstract

In cancer progression, metastasis is a major cause of poor survival of patients and can be targeted for therapeutic interventions. The first discovered metastatic-suppressor Nm23-H1 possesses nucleoside diphosphate kinase, histidine kinase, and DNase activity as a broad-spectrum enzyme. Recent advances in cancer metastasis have opened new ways for the development of therapeutic molecular approaches. In this review, we provide a summary of the current understanding of Nm23/NDPKs in the context of viral oncogenesis. We also focused on Nm23-H1-mediated cellular events with an emphasis on chromatin modifications. How Nm23-H1 modulates the activities of chromatin modifiers through interaction with Epstein–Barr virus-encoded oncogenic antigens and related crosstalks are discussed in the context of other oncogenic viruses. We also described the current understanding of the cellular and viral interactions of Nm23-H1 and their reference to transcription regulation and metastasis. Further, we summarized the recent therapeutic approaches targeting Nm23 and its potential links to pathways that can be exploited by oncogenic viruses.

EBNA3C facilitates RASSF1A downregulation through ubiquitin-mediated degradation and promoter hypermethylation to drive B-cell proliferation

“…Earlier studies in our lab showed that DNMT3A and DNMT3B, but not DNMT1, gradually increased in EBV primary infected-B cells [37]. Furthermore, studies in our lab showed that EBNA3C not only increased the expression of DNMT1 but also interacted with DNMT1 in EBNA3C-expressing cell lines [56]. In this study, we confirmed that DNMT1 was slightly increased in EBNA3C stably expressing BJAB7 and BJAB10 cell lines.…”

“…Previous data from our lab have shown that EBNA3C could interact with DNMT1 and induce DNMT1 expression [56]. Earlier studies also showed that silencing DNMT1 could upregulate RASSF1A expression and suppress RASSF1A methylation in esophageal squamous cell carcinoma [75].…”

“…Conflicting results were obtained with LMP1 in regulating DNMTs expression [53, 77]. LMP2A and EBNA3C were also shown to induce DNMT1 expression [55, 56]. However, the details as to the mechanism of RASSF1A inhibition is still not fully understood.…”

“…LMP2A, another EBV-encoded latent nuclear membrane protein, was also shown to upregulate DNMT1 expression and to enhance methylation of the PTEN promoter [55]. Previous studies in our lab showed that EBNA3C not only upregulated the expression of DNMT1 but also interacted with DNMT1 [56]. However, whether EBNA3C or another latent nuclear protein encoded by EBV inhibits expression, and associated functions of RASSF1A by increasing DNMT1 level remains unclear.…”

The NDPK/NME superfamily: state of the art

“…[48][49][50][51][52][53][54][55] The interactions of NDPK with components of the cytoskeletal machinery are highly relevant, given the well-established role of the cytoskeleton in cell motility, a critical determinant of the metastasis process. NME1 has also been reported to bind proteins belonging to small and heterotrimeric G-proteins ( [56][57][58][59][60][61] ; and Filic 62 upcoming issue; Abu-Taha et al, 63 this issue), transcriptional complexes ( 64-69 ; Sharma et al, 70 Pandey and Robertson, 71 and Puts et al, 72 all in this issue), and components of signaling pathways of MAPK, [73][74][75] TGF-β [76][77][78] and Notch, 79 as well as other factors promoting invasion and metastasis ( 80,81 ; Ferrucci et al 82 upcoming issue). Accordingly, the list of protein/protein interactions involving NME1 is huge and could yield new information about the anti-metastatic activity of NME1, and more generally about the metastatic process.…”