Oncotarget

Research Papers:

Counteracting survival functions of EBNA3C in Epstein-Barr virus (EBV)-driven lymphoproliferative diseases by combination of SAHA and bortezomib

Kwai Fung Hui, Po Ling Yeung, Kam Pui Tam and Alan Kwok Shing Chiang _

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Oncotarget. 2018; 9:25101-25114. https://doi.org/10.18632/oncotarget.25341

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Abstract

Kwai Fung Hui1,*, Po Ling Yeung1,*, Kam Pui Tam1 and Alan Kwok Shing Chiang1

1Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China

*These authors contributed equally to this work

Correspondence to:

Alan Kwok Shing Chiang, email: chiangak@hku.hk

Keywords: bortezomib; SAHA; Epstein-Barr virus; lymphoproliferative disease; EBNA3

Received: June 05, 2017     Accepted: April 06, 2018     Published: May 18, 2018

ABSTRACT

Combination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes. Isobologram analysis showed that SAHA/bortezomib induced significantly greater synergistic killing of EBNA3C-revertant cells when compared with EBNA3C-knockout cells. Such differential response was not observed in either EBNA3A or -3B revertant versus their knockout pairs. Interestingly, EBNA3C-knockout cells showed significant G2/M arrest whilst EBNA3C-revertant cells and LCLs escaped G2/M arrest induced by SAHA/bortezomib and became more susceptible to the induction of apoptosis. In parallel, SAHA/bortezomib induced stronger expression of p21WAF1 but weaker expression of p-cdc25c, an M-phase inducer phosphatase, in EBNA3C-expressing cells when compared with EBNA3C-knockout cells. SAHA/bortezomib also induced greater growth suppression of EBNA3C-expressing xenografts (EBNA3C-revertant and LCL) than that of EBNA3C-knockout xenografts in SCID mice. In conclusion, our data showed that SAHA/bortezomib could synergistically induce killing of BL and LCL through counteracting the survival functions of EBNA3C, providing a strong basis for clinical testing of this drug combination in patients with EBV-associated lymphoproliferative diseases.


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