SETDB2 participates in iron metabolism in esophageal squamous cell carcinoma via H3K9me3-mediated TFRC silencing

SET domain bifurcated histone lysine methyltransferase 2 (SETDB2) gene is located within the 13q14.2 genomic copy number deletion locus in esophageal squamous cell carcinoma (ESCC), yet its potential role and the underlying mechanism in tumorigenesis remain unclear. Here, we found that the copy number deletion of SETDB2 was significantly associated with poor prognosis of ESCC patients. Its expression was decreased in tumors compared with adjacent non-tumorous tissues. As an ESCC tumor suppressor gene, SETDB2 was able to inhibit cell proliferation and reduce aggressiveness in vitro and in vivo. Moreover, we had identified transferrin receptor (TFRC) as a downstream target of SETDB2, which was downregulated by SETDB2 through two distinct H3K9me3 modification sites within its promoter region. Furthermore, our findings revealed that SETDB2 modulated cellular iron metabolism through TFRC-STEAP3-DMT1 signaling axis in ESCC cells. SETDB2 could improve cellular Fe²⁺ and ROS levels, whereas TFRC exhibited an opposite effect. As a key mediator connecting SETDB2 and iron metabolism in ESCC progression, TFRC knocking-down can rescue cell proliferation rate changes caused by SETDB2 knocking-down as well. Our results not only elucidated the role of SETDB2 methyltransferase in ESCC tumorigenesis by regulating cellular iron homeostasis through H3K9me3 modification, but also highlighted the potential of iron chelation-based anticancer therapy for ESCC patients with SETDB2 copy number deletion in clinical treatment.