C/EBPβ Is a Transcriptional Regulator of Wee1 at the G₂/M Phase of the Cell Cycle

Cells. 2019 Feb 11;8(2):145. doi: 10.3390/cells8020145.


The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G₂/M transition in the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with simultaneously increased Wee1 and decreased Cdc25B expression. Chromatin immunoprecipitation (ChIP) analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through its interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G₂/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G₂/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.

Keywords: C/EBPβ; G2/M arrest; Wee1; Y15-pCDK1; cell cycle; lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • CDC2 Protein Kinase / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Proteins / metabolism*
  • Cell Division* / drug effects
  • Cell Division* / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • G2 Phase* / drug effects
  • G2 Phase* / genetics
  • Histone Deacetylase 2 / metabolism
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Mice, Nude
  • Middle Aged
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrazoles / pharmacology
  • Pyrimidinones / pharmacology
  • Transcription, Genetic / drug effects


  • CCAAT-Enhancer-Binding Protein-beta
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Pyrazoles
  • Pyrimidinones
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 2
  • adavosertib