TFAP2A-mediated Transcriptional Activation of ELMO1 Inhibits Ferroptosis and Promotes Esophageal Squamous Cell Carcinoma Progression

The role of engulfment and cell motility protein 1 (ELMO1) in esophageal squamous cell carcinoma (ESCC) is still unknown, even though it is critical for cellular behaviors. Our bioinformatics analyses have predicted transcription factor AP-2 alpha (TFAP2A) as a potential upstream regulator of ELMO1, suggesting its involvement in ESCC progression. ELMO1 expression in ESCC cells was analyzed. Lentivirus-mediated gene silencing was conducted, while cell counting kit-8, wound healing, and transwell assays evaluated the effects of ELMO1 on ESCC cell activities. The transcriptional regulatory effect of TFAP2A on ELMO1 was verified using dual-luciferase reporter assays and ChIP-qPCR. Additionally, ferroptosis-related indicators were detected to explore the potential role of TFAP2A/ELMO1 in ESCC. A nude mouse xenograft model was established to analyze tumor growth in vivo. ELMO1 was upregulated in KYSE150 cells. Silencing of ELMO1 suppressed ESCC cell migration and invasion, while sensitizing cells to ferroptosis. TFAP2A transcriptionally activated ELMO1 by binding to its promoter, thereby enhancing ESCC cell invasive potential. In vivo, TFAP2A knockdown activated ferroptosis and inhibited tumor growth, whereas ELMO1 overexpression promoted tumor progression. TFAP2A facilitates ESCC cell proliferation, migration, and invasion by promoting ELMO1 transcription and inhibiting ferroptosis. Both TFAP2A and ELMO1 act as oncogenic drivers in ESCC and may represent potential therapeutic targets. TFAP2A acts as a transcriptional activator of ELMO1 in esophageal squamous cell carcinoma (ESCC) cells. By upregulating ELMO1 expression, TFAP2A reduces the sensitivity of ESCC cells to ferroptosis, thereby promoting tumor cell survival and progression. Conversely, knockdown of TFAP2A inhibits ELMO1 transcription, increases ferroptosis sensitivity, and suppresses tumor cell growth. Note: ESCC, esophageal squamous cell carcinoma; TFAP2A, transcription factor AP-2 alpha; ELMO1, the role of engulfment and cell motility protein 1.