2659 - AARS1-Mediated Histone H3K18 Lactylation Regulates Esophageal Squamous Cell Carcinoma Radioresistance via ALDH3B1-Dependent Ferroptosis
Presenter(s)
Y. Xie1,2, B. Tian1, J. Yuan1, Y. Xu1, F. Wang1, J. Yu1, and D. Chen1; 1Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 2Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Purpose/Objective(s): Radioresistance is the primary barrier to radiotherapy in esophageal squamous cell carcinoma (ESCC), significantly affecting the therapeutic efficacy and prognosis of ESCC patients. While histone lactylation has emerged as a critical epigenetic regulator in malignant tumors in recent reports, its role in ESCC radiosensitivity remains unexplored. This study investigates whether the AARS1-H3K18 lactylation (H3K18la)-ALDH3B1 axis modulates radioresistance through ferroptosis regulation.
Materials/Methods: Pan-lactylation levels were assessed by immunohistochemistry (IHC) in ESCC patients receiving radiotherapy. The ESCC cell lines KYSE150 and KYSE450 were selected to construct radioresistant cell lines and stably transduced cell lines with overexpression or knockdown of genes via the lentivirus system. Radiosensitivity was evaluated via colony formation, CCK-8, western blot, and nude mice xenograft tumor models. Chromatin immunoprecipitation (ChIP), ChIP sequencing (ChIP-seq), and ChIP-quantitative polymerase chain reaction (ChIP-qPCR) identified H3K18la-targeted genes. Lipid peroxidation and ferroptosis markers were measured by flow cytometry and fluorescence microscopy.
Results: Pan-lactylation levels were elevated in ESCC cancer tissues compared to para-cancer tissues from patients receiving radiotherapy, with higher levels correlating with poor prognosis and radiotherapy response (p<0.05). Both pan-lactylation and H3K18la were upregulated in radioresistant ESCC cells. AARS1 was identified as the H3K18la "writer" and was upregulated in radioresistant ESCC cells. AARS1 overexpression promoted radioresistance, while its knockdown enhanced radiosensitivity. ChIP-seq analysis combined with ChIP-qPCR validation revealed ALDH3B1 as a direct transcriptional target regulated by H3K18la. ALDH3B1 overexpression enhanced radioresistance, whereas its knockdown enhanced radiosensitivity. Mechanistically, ALDH3B1 suppressed lipid peroxidation and ferroptosis in ESCC cells, thereby conferring radioresistance.
Conclusion: This study reveals a therapeutically targetable axis wherein AARS1-mediated H3K18 lactylation transcriptionally upregulates ALDH3B1, which suppresses ferroptosis to drive ESCC radioresistance. Targeting this epigenetic-metabolic crosstalk of the AARS1-H3K18la-ALDH3B1-ferroptosis axis represents a promising strategy to improve radiotherapy efficacy in ESCC patients.