Among six histone methyltransferase inhibitors, we identified that chaetocin exerted robust anti-cancer in vitro and in vivo by inhibiting tumor cell proliferation and inducing apoptosis and G1 phase cell cycle arrest via the suppression of the KMT1A–GATA3–STAT3 circuit and other stemness-related pathways. The gene discussed is GATA3; the disease is neoplasm.