SEPT9 as a therapeutic target for enhancing radiotherapy efficacy in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, where radiotherapy is a key treatment modality. However, radioresistance significantly limits its efficacy, leading to treatment failure. Septin9 (SEPT9), a cytoskeletal regulatory protein, has been implicated in various cancers, with its methylation status serving as a biomarker for diagnosis and prognosis. While extensively studied in colorectal cancer, the role of SEPT9 and its methylation in ESCC remains unclear. This study aimed to investigate the role of SEPT9 in ESCC and its potential as a predictive biomarker. SEPT9 expression and methylation levels were analyzed in 80 ESCC patients undergoing radiotherapy using qMS-PCR and immunohistochemistry (IHC). Functional experiments using SEPT9-knockout (KO) and overexpressing (Sep) ESCC cell lines were conducted in in vitro and in vivo models. The results demonstrated that SEPT9 overexpression enhances radiosensitivity, while SEPT9-knockout promotes radioresistance. Additionally, higher SEPT9 methylation correlated with radioresistance and poor survival. These findings indicate a potential association between SEPT9 methylation and radiotherapy response in ESCC. While promising, further validation is needed before SEPT9 methylation can be established as a reliable clinical biomarker or therapeutic target.