CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity

Area of Science:

• Immunology
• Epigenetics
• Gastroenterology

Background:

• Interferon-gamma (IFNγ) is vital for gut homeostasis, but its dysregulation is linked to colon pathologies like colitis and colorectal cancer (CRC).
• The epigenetic regulator CBX3 (HP1γ) role in colon inflammation and CRC remains unclear.

Purpose of the Study:

• To investigate the role of CBX3 in regulating IFNγ signaling in the colon epithelium.
• To determine CBX3's impact on colon inflammation and CRC chemo-resistance.

Main Methods:

• Investigated CBX3's effect on IFNγ-responsive genes STAT1 and CD274 (PD-L1) in colon epithelial cells.
• Utilized CBX3 deletion mouse models for colon inflammation studies.
• Employed chromatin immunoprecipitation to assess CBX3 binding to gene promoters.
• Evaluated CRC cell and tumor model sensitivity to IFNγ and chemotherapy.

Main Results:

• CBX3 transcriptionally represses STAT1 and CD274 (PD-L1), key IFNγ-responsive genes.
• CBX3 deletion leads to chronic colon inflammation with increased STAT1 and CD274 expression.
• IFNγ reduces CBX3 binding to STAT1 and CD274 promoters, priming gene expression.
• CBX3 deletion enhances CRC cell sensitivity to IFNγ, improving chemotherapy outcomes in vitro and in vivo.

Conclusions:

• CBX3 acts as an antagonist to IFNγ signaling in the colon epithelium by repressing STAT1 and PD-L1.
• CBX3 plays a role in modulating colon inflammatory responses and CRC chemo-resistance.
• Targeting CBX3 could be a strategy to enhance IFNγ-based therapies for CRC.