Induction of Epstein-Barr virus thymidine kinase expression and tumorigenicity of nasopharyngeal carcinoma cells by histone deacetylase inhibitors

Objectives Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated malignancy encoding a virus-induced protein with thymidine kinase (TK) activity. This study aimed to assess that treatment of EBV-associated NPC cell lines with histone deacetylase inhibitors (HDACI) led to induction of the EBV lytic gene expression, including expression of the EBV TK.

Methods The EBV+NPC cell line, NA, and the parental EBV−NPC cell line, TW01. To induce EBV lytic cycle, cells were treated with either trichostatin A (TSA), valproic acid (VPA) or suberoylanilide hydroxamic acid (SAHA) for passage 5 to15 and then incubated with [³H]FEAU. Cell uptake was expressed as the accumulation ratio cpm/mg of total proteins divided by the cpm/g (ml) of medium]. Cells (5x10⁶) were resuspended in 100-μl Matrigel matrix and injected s.c. on the shoulder of nude mice. During the 15 recurrent cycles, the microPET imaging of [¹⁸F]FEAU were done when tumors reached a size of ~1 cm in diameter.

Results In vitro cellular studies revealed slightly uptake of [³H]FEAU in the EBV+NPC cell line treated with SAHA (1.05~1.12-fold) and VPA (1.02~1.16 -fold) at passage 5 to 15 incubation. The uptake of [¹⁸F]FEAU in EBV+NPC tumor (NA) was weakly higher than that of EBV−NPC tumor (TW01) at 1 h p.i.. The tumor accumulation ratio slightly increased with SAHA and VPA treatment in EBV+NPC tumor.

Conclusions HDACI has the potential to activate viral lytic gene (EBV-TK) expression and weakly trigger the switch of EBV from latent to lytic cycle. Anti-viral drug combined with HDACI might provide a potential targeted therapeutic stragegy against EBV-associated NPC