Abstract
Dysregulation of histone demethylation is a pivotal epigenetic event driving malignant tumor progression. Thus, it is critical to understand the downstream signaling pathways that govern dysregulation of histone demethylation. Here, we identified KDM4A as the exclusively and significantly up-regulated member in testicular germ cell tumors (TGCTs) through a pan-family expression screen of histone demethylases (KDM1-8 and JMJD6) using the GEPIA database. KDM4A knockdown markedly inhibits TGCT cell migration and invasion in vitro, and metastatic potential in vivo. Mechanistically, KDM4A induces H3K9me3 demethylation at the CCL3 promoter, thereby restoring chromatin accessibility to facilitate STAT1-dependent CCL3 transcriptional activation, which activates the PI3K/AKT pathway, ultimately promoting focal adhesion turnover and enhancing cellular invasiveness. Furthermore, in a lung metastasis model, KDM4A significantly promoted distal colonization of TGCT in a CCL3-dependent manner. Summary, our findings reveal that KDM4A is a critical epigenetic regulator of TGCT metastasis, driving tumor progression via the STAT1-dependent CCL3 transcriptional activation, which promotes focal adhesion turnover by PI3K/AKT axis. Hence, targeting KDM4A may be a promising therapeutic strategy for improving the clinical prognosis of patients with metastatic TGCT.