KDM4D enhances radiosensitivity in esophageal squamous cell carcinoma through the SRBD1/RPL11/c-Myc/WIP1/CHK1 axis

Background: Radioresistance is a critical challenge in the treatment of esophageal squamous cell carcinoma (ESCC). Histone lysine-specific demethylase 4D (KDM4D) has been implicated in DNA damage response; however, its role in regulating ESCC radiosensitivity remained unclear. We hypothesized KDM4D modulates radiosensitivity through the c-Myc/checkpoint kinase 1 (CHK1) pathway. Objective: To investigate the role of KDM4D in ESCC radiosensitivity and to elucidate the underlying molecular mechanisms. Methods: KDM4D expression was analyzed in tumor samples from 32 ESCC patients who received neoadjuvant radiotherapy. ESCC cell lines with KDM4D knockdown or overexpression were subjected to irradiation, and radiosensitivity was evaluated. Chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR), luciferase assay, and xenograft models were used to explore the underlying mechanisms. Results: Elevated KDM4D expression was associated with improved response to radiotherapy and prolonged progression-free survival (PFS). KDM4D knockdown significantly reduced radiation-induced apoptosis. Mechanistically, KDM4D promoted the demethylation of histone H3 lysine 9 trimethylation (H3K9me3), thereby activating S1 RNA-binding domain-containing protein 1 (SRBD1). SRBD1 subsequently upregulated ribosomal protein L11 (RPL11), which suppressed c-Myc expression, thereby downregulating wild-type p53-induced phosphatase 1 (WIP1) and CHK1. Rescue experiments and xenograft studies further verified this regulatory axis. Conclusion: KDM4D enhances ESCC radiosensitivity through the SRBD1/RPL11/c-Myc/WIP1/CHK1 pathway, highlighting its potential as both a diagnostic biomarker and a therapeutic target.