While RHBDD1 promotes colorectal cancer (CRC) via TGFα/EGFR/ERK signaling (Song et al., 2015), our study reveals a distinct mechanism in ESCC, where RHBDD1 enhances invasion by activating Wnt/β-catenin via ELK3. Here, RHBDD1 is linked to esophageal squamous cell carcinoma.