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

Author:

Xiang Yao,Mata-Garrido JorgeORCID,Fu YuanjiORCID,Desterke ChristopheORCID,Batsché EricORCID,Hamaï Ahmed,Sedlik Christine,Sereme Youssouf,Skurnik David,Jalil AbdelaliORCID,Onifarasoaniaina RachelORCID,Frapy Eric,Beche Jean-Christophe,Alao Razack,Piaggio Eliane,Arbibe Laurence,Chang YunhuaORCID

Abstract

AbstractAs an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes’ transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.

Funder

CSC | Chinese Government Scholarship

Agence Nationale de la Recherche

Institut National de la Santé et de la Recherche Médicale

Publisher

Springer Science and Business Media LLC

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