Zhu X I, Huang Kai, Kao Xiaoming, Tang Zhaohui, Guo Wenjie, Wu Tiancong, Li Qiurong
Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, China.
Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China.
Oncol Res. 2025 Apr 18;33(5):1149-1159. doi: 10.32604/or.2024.054930. eCollection 2025.
Colorectal cancer (CRC) holds the third position in global cancer prevalence mortality. Although chemotherapy is a conventional treatment, recent investigations have shed light on the therapeutic potential of the cGAS cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in CRC management. Despite the primary role of the death domain-associated protein (Daxx) in cellular apoptosis, its influence on the regulation of cGAS-STING activation remains elusive.
The Daxx degradation and speck formation were conducted using immunofluorescence and Western blotting. The Daxx knock-down and over-expression in CRC cells were performed to detect and migration, proliferation, cGAS-STING activation, and immune responses.
Our study reveals that treatment with irinotecan (CPT-11) and oxaliplatin (OXA) significantly accelerated the Daxx degradation and diminished the formation of Daxx specks within the nucleus of CRC cells. Genetic elimination of Daxx enhanced the irinotecan and oxaliplatin-induced suppression of proliferation and migration in CRC cells, and overexpression of Daxx resulted in similar results. Mechanistically, Daxx overexpression reduced DNA damage repair by restraining homologous recombination (HR) over non-homologous end-joining (NHEJ), which suppressed TBK1 and IRF3 phosphorylation downstream of the cGAS-STING signal. In a murine model of CT-26 tumors, Daxx knockdown amplified the OXA-mediated tumor growth inhibition by promoting STING activation and immune responses.
Our findings show that the degradation of nuclear Daxx potentiates the cGAS-STING pathway, thereby bolstering the efficacy of chemotherapy.
结直肠癌（CRC）在全球癌症患病率死亡率中位居第三。尽管化疗是一种传统治疗方法，但最近的研究揭示了环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路在CRC治疗中的潜在治疗作用。尽管死亡结构域相关蛋白（Daxx）在细胞凋亡中起主要作用，但其对cGAS-STING激活调节的影响仍不清楚。
采用免疫荧光和蛋白质免疫印迹法检测Daxx降解和斑点形成。在CRC细胞中进行Daxx基因敲低和过表达，以检测细胞迁移、增殖、cGAS-STING激活和免疫反应。
我们的研究表明，伊立替康（CPT-11）和奥沙利铂（OXA）治疗显著加速了Daxx降解，并减少了CRC细胞核内Daxx斑点的形成。Daxx基因消除增强了伊立替康和奥沙利铂诱导的CRC细胞增殖和迁移抑制，Daxx过表达也得到了类似结果。机制上，Daxx过表达通过抑制同源重组（HR）而非非同源末端连接（NHEJ）减少DNA损伤修复，从而抑制cGAS-STING信号下游的TBK1和IRF3磷酸化。在CT-26肿瘤小鼠模型中，Daxx基因敲低通过促进STING激活和免疫反应增强了OXA介导的肿瘤生长抑制。
我们的研究结果表明，细胞核Daxx的降解增强了cGAS-STING通路，从而提高了化疗疗效。
