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

Abstract

BACKGROUND:

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.

METHODS:

Abnormal 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.

RESULTS:

CENP-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.

CONCLUSIONS:

The 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.

• Authors: Cheng-Lin Qi, Mao-Ling Huang, You Zou, Rui Yang, Yang Jiang, Jian-Fei Sheng, Yong-Gang Kong, Ze-Zhang Tao, Hong-Yan Feng, Qing-Quan Hua, Li-Hong Bu, Shi-Ming Chen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 390 (Dec 10 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34893086 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• CENPN protein, human
• Chromosomal Proteins, Non-Histone
• Interferon Regulatory Factor-2
• Irf2 protein, mouse
• Recombinant Proteins
• TBI protein, recombinant
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis
• Cell Cycle
• Cell Proliferation
• Chromosomal Proteins, Non-Histone (metabolism)
• Genes, Synthetic
• Humans
• Interferon Regulatory Factor-2 (metabolism)
• Mice
• Mice, Nude
• Nasopharyngeal Neoplasms (genetics)
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• Recombinant Proteins
• Signal Transduction
• Warburg Effect, Oncologic