PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma

Meng-Yao Wang,Bin Qi,Fang Wang,Zhi-Rui Lin,Ming-Yi Li,Wen-Jing Yin,Yan-Yi Zhu,Lu He,Yi Yu,Fang Yang,Jin-Quan Liu,Dong-Ping Chen

doi:10.1038/s41389-020-00293-9

Meng-Yao Wang, Bin Qi + Show 10 more

Open Access

https://doi.org/10.1038/s41389-020-00293-9

Copy DOI

Abstract

CD276 (also known as B7–H3, an immune checkpoint molecule) is aberrantly overexpressed in many cancers. However, the upregulation mechanism and in particular, whether oncogenic signaling has a role, is unclear. Here we demonstrate that a pro-oncogenic kinase PBK, the expression of which is associated with immune infiltration in nasopharyngeal carcinoma (NPC), stimulates the expression of CD276 epigenetically. Mechanistically, PBK phosphorylates MSL1 and enhances the interaction between MSL1 and MSL2, MSL3, and KAT8, the components of the MSL complex. As a consequence, PBK promotes the enrichment of MSL complex on CD276 promoter, leading to the increased histone H4 K16 acetylation and the activation of CD276 transcription. In addition, we show that CD276 is highly upregulated and associated with immune infiltrating levels in NPC. Collectively, our findings describe a novel PBK/MSL1/CD276 signaling axis, which may play an important role in immune evasion of NPC and may be targeted for cancer immunotherapy.

Highlights

Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancers in southeast Asia and north Africa[1,2]
PDZ-binding kinase (PBK) expression is associated with immune infiltration The level of tumorinfiltrating lymphocytes (TILs) is an independent predictor of sentinel lymph node status and survival in many cancers including NPC44
To explore the role of PBK in immune regulation of NPC, we investigated whether PBK expression was correlated with immune infiltration levels in NPC

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancers in southeast Asia and north Africa[1,2]. The standard treatment for patients with NPC is concurrent chemoradiation preceded or followed by systemic chemotherapy, according to the National Comprehensive Cancer Network (NCCN) guidelines. The local control rate has been significantly improved, approximately 30–40% of patients with locoregionally advanced NPC eventually develop distant metastasis after receiving radical treatment[3]. Novel strategies are alarmingly needed for NPC patients with a high risk of distant metastasis. Epstein–Barr virus (EBV) infection is a major risk factor for the development of NPC in the endemic regions[6,7], upregulation of programmed cell death-ligand 1 (PDL1)

Methods

Results

Conclusion