Ubiquitin-proteasome degradation and histone modification promote the downregulation of SNPH in RR ESCC cells. Dephosphorylation of CREB promotes the re-expression of SNPH, which induces radiosensitization. Moreover, the expression of SNPH is related to the radiotherapy efficacy in esophageal squamous cell carcinoma and is an independent prognostic factor for patients with esophageal squamous cell carcinoma. Here, CREB1 is linked to esophageal squamous cell carcinoma.