Overexpression of JMJD6 drives immune evasion via the BRD4-IRF1-PD-L1 axis and promotes malignancy in gastric cancer.

JMJD6, a Jumonji C domain-containing protein located in the cancer-amplified region 17q25, has emerged as a putative oncogene in several malignancies. Only a few reports identified its function in GC (gastric cancer). In this study, we analyzed the detail oncogenic and immunosuppressive roles of JMJD6 and clinical relevance in GC. We analyzed six GC cell lines and 174 primary tumors. Overexpression of JMJD6 was frequently detected in GC cell lines (4/6 cell lines, 66.7%) and 69 primary GC specimens. Overexpression of JMJD6 was significantly associated with advanced tumor stage and was an independent poor prognostic factor (P < 0.001, Hazard ratio 4.15). Knockdown of JMJD6 suppressed GC cell proliferation, migration and invasion in a TP53 mutation-independent manner, and reduced PD-L1 (Programmed cell death ligand 1) expression via BRD4 (Bromodomain-containing protein 4) and IRF1 (Interferon regulatory factor 1) down-regulation. Ectopic overexpression of JMJD6 induced PD-L1 expression via BRD4 and IRF1 upregulation in low-PD-L1-expressing cells. In co-culture assays with activated T cells, JMJD6 knockdown enhanced tumor immunogenicity and T cell-mediated cytotoxicity. In primary GC samples, JMJD6 expression correlated positively with PD-L1 expression. These findings suggest that JMJD6 functions as a dual regulator of tumor aggressiveness and immune escape, highlighting its utility as a prognostic factor and a promising therapeutic target in GC.