As 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.

中文翻译：

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CBX3 拮抗 IFNγ/STAT1/PD-L1 轴来调节结肠炎症和结直肠癌化疗敏感性。


作为一种重要的免疫刺激剂和调节剂，IFNγ 对于肠道稳态至关重要，其失调与结肠炎和结直肠癌 (CRC) 等多种结肠病理有关。在这里，我们证明表观遗传调节因子 CBX3（也称为 HP1γ）通过转录抑制两个关键的 IFNγ 反应基因：STAT1 和 CD274（编码程序性死亡配体 1，PD-L1）来拮抗结肠上皮中的 IFNγ 信号传导。因此，CBX3 缺失导致小鼠慢性结肠炎症，并伴有 STAT1 和 CD274 表达上调。染色质免疫沉淀表明 CBX3 与 STAT1 和 CD274 启动子结合以抑制其表达。相反，IFNγ 显着减少 CBX3 与这些启动子的结合并引发基因表达。 CBX3 和 IFNγ 对 STAT1/PD-L1 表达的拮抗作用也在结直肠癌中观察到。引人注目的是，CBX3 缺失增强了 CRC 细胞对 IFNγ 的敏感性，最终增强了 CRC 细胞体外和同基因小鼠肿瘤模型体内 IFNγ 刺激下的化疗敏感性。总体而言，这项工作揭示了通过负向调节 IFNγ 刺激的免疫基因的转录，CBX3 参与调节结肠炎症反应和结直肠癌化疗耐药。