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

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.