The IRF2/CENP-N/AKT signaling axis promotes proliferation, cell cycling and apoptosis resistance in nasopharyngeal carcinoma cells by increasing aerobic glycolysis

Cheng-Lin Qi,Rui Yang,Yong-Gang Kong,Shi-Ming Chen,Jian-Fei Sheng,Ze-Zhang Tao,You Zou,Qing-Quan Hua,Yang Jiang,Mao-Ling Huang,Hong-Yan Feng,Li-Hong Bu

doi:10.1186/s13046-021-02191-3

Abstract

BackgroundCentromere protein N (CENP-N) has been reported to be highly expressed in malignancies, but its role and mechanism in nasopharyngeal carcinoma (NPC) are unknown.MethodsAbnormal CENP-N expression from NPC microarrays of GEO database was analyzed. CENP-N expression level was confirmed in NPC tissues and cell lines. Stable CENP-N knockdown and overexpression NPC cell lines were established, and transcriptome sequencing after CENP-N knockdown was performed. In vitro and in vivo experiments were performed to test the impact of CENP-N knockdown in NPC cells. ChIP and dual luciferase reporter assays were used to verify the combination of IRF2 and CENP-N. Western blot analysis, cellular immunofluorescence, immunoprecipitation and GST pulldown assays were used to verify the combination of CENP-N and AKT.ResultsCENP-N was confirmed to be aberrantly highly expressed in NPC tissues and cell lines and to be associated with high 18F-FDG uptake in cancer nests and poor patient prognosis. Transcriptome sequencing after CENP-N knockdown revealed that genes with altered expression were enriched in pathways related to glucose metabolism, cell cycle regulation. CENP-N knockdown inhibited glucose metabolism, cell proliferation, cell cycling and promoted apoptosis. IRF2 is a transcription factor for CENP-N and directly promotes CENP-N expression in NPC cells. CENP-N affects the glucose metabolism, proliferation, cell cycling and apoptosis of NPC cells in vitro and in vivo through the AKT pathway. CENP-N formed a complex with AKT in NPC cells. Both an AKT inhibitor (MK-2206) and a LDHA inhibitor (GSK2837808A) blocked the effect of CENP-N overexpression on NPC cells by promoting aerobic glycolysis, proliferation, cell cycling and apoptosis resistance.ConclusionsThe IRF2/CENP-N/AKT axis promotes malignant biological behaviors in NPC cells by increasing aerobic glycolysis, and the IRF2/CENP-N/AKT signaling axis is expected to be a new target for NPC therapy.

Highlights

Centromere protein N (CENP-N) has been reported to be highly expressed in malignancies, but its role and mechanism in nasopharyngeal carcinoma (NPC) are unknown
We found the Interferon regulatory factor 2 (IRF2)/centromere protein (CENP)-N/ Protein kinase B (AKT) axis promotes malignant biological behaviors in NPC cells by increasing aerobic glycolysis, the IRF2/ CENP-N/AKT signaling axis is expected to be a new target for NPC therapy
CENP‐N was significantly upregulated in NPC and was related to high glucose metabolism and poor prognosis To investigate the role of gene expression abnormalities in the development and progression of NPC, we selected two sequencing microarrays from the Gene Expression Omnibus (GEO) database for Differentially expressed genes (DEGs) analysis

Summary

Introduction

Centromere protein N (CENP-N) has been reported to be highly expressed in malignancies, but its role and mechanism in nasopharyngeal carcinoma (NPC) are unknown. Head and neck squamous cell carcinoma (HNSCC) is a general term for cancers that occur in the anatomical areas of the nasal cavity, lips, tongue, oral cavity, pharynx, and larynx and arise from the malignant transformation of mucosal epithelium [1]. Nasopharyngeal carcinoma (NPC) is a subtype of HNSCC initiated by the malignant transformation of nasopharyngeal mucosal epithelial cells. There are still more unknown target genes and specific molecular biological mechanisms of action involved in regulating the development and progression of NPC; a proportion of patients with NPC still have a poor prognosis when treated with combination therapy.

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