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Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer

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机构： [1]Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China [2]Department of Hematology, West China Hospital, Sichuan University, Chengdu, China

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关键词： Kdm4a ML324 Bladder cancer Sqle ROS Oxidative stress

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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.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

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出版当年[2023]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学

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第一作者机构： [1]Department of Urology, Institute of Urology, Sichuan Clinical Research Center for Urological and Kidney Diseases, West China Hospital, Sichuan University, Chengdu, China

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