Background: Atonal bHLH transcription factor 8 (ATOHB) plays heterogenous roles in different types of cancer, but its function and molecular mechanism in esophageal squamous cell carcinoma (ESCC) remain to be clarified. Methods: ATOH8 expression was analyzed using TCGA data and experimental assays. Its functional impact was assessed through in vitro assays (CCK-8, transwell) and in vivo mouse models (xenograft, lung metastasis). Molecular interactions between ATOH8, OCT4, and TFAP2A were characterized using co-immunoprecipitation (Co-IP), ubiquitination, lucif-erase, and chromatin immunoprecipitation (ChIP) assays. Results: Our results revealed that ATOH8 was significantly downregulated in ESCC. ATOH8 overexpression effectively inhibited the viability, mobility, and epithelial-mesenchymal transition (EMT) and promoted apoptosis of ESCC cells in vitro. Similarly, in vivo experiments suggested that the growth of xenograft tumors and lung metastasis were substantially suppressed by overexpressing ATOH8. Mechanistically, ATOH8 was confirmed to negatively regulate the protein stability of OCT4 by promoting its ubiquitination. The inhibitory effect of ATOH8 on ESCC aggressiveness was partially abrogated when OCT4 was overexpressed. Moreover, we found that ATOH8 deficiency in ESCC was caused by TFAP2A-induced transcriptional suppression. Conclusion: Our results demonstrated a critical role of the TFAP2A-ATOH8-OCT4 signaling axis in the aggressiveness of ESCC. Specifically, TFAP2A-mediated suppression of ATOH8 expression facilitated OCT4-induced EMT and tumor progression. These findings offer insights to identify ATOHB as a novel biomarker for ESCC management.
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