[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 gastric cancer (GC). In this study, we investigated the oncogenic and immunosuppressive roles of JMJD6 and its clinical relevance in GC. We analyzed 6 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 programmed death-ligand 1 (PD-L1) expression via bromodomain-containing protein 4 (BRD4) and interferon regulatory factor 1 (IRF1) 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.