BET bromodomain inhibitor JQ1 preferentially suppresses EBV-positive nasopharyngeal carcinoma cells partially through repressing c-Myc

Ning Li,Lin Feng,Ling-Rui Liu,Xiaoming Xie,Xinhua Xie,Yi-Xin Zeng,Xue-Kang Qi,Yu-Xin Lin,Qi-Sheng Feng,Gui-Ping He,Lu Yang

doi:10.1038/s41419-018-0789-1

Abstract

The management of advanced nasopharyngeal carcinoma (NPC) remains a challenge. The ubiquitous nature of Epstein–Barr virus (EBV) infection in nonkeratinizing NPC has forced us to investigate novel drugs for NPC in the presence of EBV. In this study, we performed a small-scale screening of a library of compounds that target epigenetic regulators in paired EBV-positive and EBV-negative NPC cell lines. We found that bromodomain and extra-terminal (BET) inhibitor JQ1 preferentially inhibits the growth of EBV-positive NPC cells. JQ1 induces apoptosis, decreases cell proliferation and enhances the radiosensitivity in NPC cells, especially EBV-positive cells. Significantly, JQ1-induced cell death is c-Myc-dependent. Notably, RNA-seq analysis demonstrated that JQ1 represses TP63, TP53 and their targets. JQ1 also lessens the expression of PD-L1 in NPC. Moreover, the high potency of JQ1 in NPC cells was further confirmed in vivo in CNE2-EBV+ tumor-bearing mice. These findings indicate that JQ1 is a promising therapeutic candidate for advanced NPC.

Highlights

Nasopharyngeal carcinoma (NPC) is a unique malignancy arising from the nasopharynx epithelium, and is highly endemic in south China and southeastern Asia[1]
Epstein–Barr virus (EBV)-positive NPC cells are highly sensitive to JQ1 To identify epigenetic-modulating agents that selectively inhibit the growth of EBV-positive NPC cells, we evaluated a panel of 16 small-molecule inhibitors that target epigenetic regulators in two pairs of EBV-positive and EBV-negative NPC cell lines, CNE2-EBV−/+ and TWO3−/+
Their targets included HDAC, LSD1, EZH2, bromodomain and extra-terminal (BET), PARP, and H3K27 histone demethylase. From this small-scale screening, we found the BET inhibitor JQ1 showed a selective effect on EBV-positive NPC cell lines (Fig. 1a)

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a unique malignancy arising from the nasopharynx epithelium, and is highly endemic in south China and southeastern Asia[1]. 15–30% of patients with NPC (>95%) in endemic regions, and shows the most consistent association with Epstein–Barr virus (EBV)[1,6]. EBV infection, EBV latent genes can lead to genetic and epigenetic alterations, eventually resulting in the development of NPC6. Epigenetics has been defined as potentially inheritable changes in gene expression that are not due to alterations in the primary sequence of DNA7. Epigenetic regulation plays a central role in control of cell fate and proliferation, and changes in epigenetic states have a major role in the development of multiple diseases, including cancer, metabolic disease, and inflammation[8].

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Results

Conclusion