Death domain-associated protein(Daxx)impairs colon cancer chemotherapy by inhibiting the cGAS-STING pathway  

作　　者：XI ZHU KAI HUANG XIAOMING KAO ZHAOHUI TANG WENJIE GUO TIANCONG WU QIURONG LI 

机构地区：[1]Research Institute of General Surgery,Jinling Hospital,Nanjing Medical University,Nanjing,210002,China [2]Research Institute of General Surgery,Nanjing Jinling Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,210002,China [3]State Key Laboratory of Pharmaceutical Biotechnology,School of Life Science,Nanjing University,Nanjing,210093,China [4]Department of Radiation Oncology,Nanjing Jinling Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,210002,China

出　　处：《Oncology Research》2025年第5期1149-1159,共11页肿瘤学研究(英文)

基　　金：supported by the National Natural Science Foundation of China(82202956)。

摘　　要：Background: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.Methods: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 in vivo and in vitro migration,proliferation,cGAS-STING activation,and immune responses.Results: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.Conclusions:Our findings show that the degradation of nuclear Daxx potentiates the cGAS-STING pathway,thereby bolstering the efficacy of chemotherapy.

关 键 词：Death domain-associated protein(Daxx) Stimulator of the interferon gene(STING) Colorectal cancer(CRC) CHEMOTHERAPY 

分 类 号：R73[医药卫生—肿瘤]