Sodium butyrate induces apoptosis enhanced by JAK2 inhibitor Fedratinib in NK/T-cell lymphoma cell.

BACKGROUND

NK/T-cell lymphoma (NKTCL) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Histone acetylation, which can regulate gene expression, plays a crucial role in epigenetic control. Sodium butyrate (NaB), a nonspecific inhibitor of histone deacetylase (HDAC), has antitumor effects on various malignancies. However, the mechanism of NaB in NKTCL remains poorly understood.

METHODS

NKTCL cells were treated with specified concentrations of NaB for designated durations. Cell viability was assessed using the CCK-8 method, whereas flow cytometry was used to evaluate apoptosis and the cell cycle. RT-qPCR and western blot analyses were conducted to measure the expression levels of genes associated with the cell cycle, apoptosis, autophagy, HDAC, EBV, and molecules in the PI3K/Akt/mTOR and JAK/STAT signaling pathways.

RESULTS

NaB downregulated the expression of HDAC 3, 4, 5, 8, 9, and 10 in NKTCL cell lines, leading to a significant reduction in cell viability and G2 phase cell cycle arrest. NaB induced apoptosis in NKTCL cell lines and inhibited the JAK/STAT signaling pathway, which was further promoted by the JAK2 inhibitor fedratinib. Moreover, NaB induced autophagy and suppressed the PI3K/Akt/mTOR signaling pathway in NKTCL cell lines. Additionally, NaB upregulated the transcription of lytic genes (TK, BMRF1, BMRF2, BRLF1, BMLF1, BNRF1, and BZLF1) in NKTCL, indicating its potential to induce EBV lytic infection.

CONCLUSIONS

NaB effectively promotes apoptosis and inhibits the JAK/STAT signaling pathway in NKTCL, which is further promoted by the JAK2 inhibitors fedratinib. Furthermore, NaB induces EBV reactivation and lytic infection in NKTCL, suggesting its ability to transition EBV from a latent to a lytic form.