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

J Exp Clin Cancer Res. 2021 Dec 10;40(1):390. doi: 10.1186/s13046-021-02191-3.

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.

Keywords: AKT; Aerobic glycolysis; CENP-N; Gglucose metabolism; IRF2; NPC.

MeSH terms

  • 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

Substances

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