Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer
Jiapeng Zhang,
Hang Xu,
Yirui He,
Xiaonan Zheng,
Tianhai Lin,
Lu Yang,
Ping Tan,
Qiang Wei
Affiliations
Jiapeng Zhang
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China
Hang Xu
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China
Yirui He
Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
Xiaonan Zheng
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China
Tianhai Lin
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China; Corresponding author.
Lu Yang
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China; Corresponding author.
Ping Tan
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China; Corresponding author.
Qiang Wei
Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China; Corresponding author.
In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer.
