KDM6A deficiency promotes 5-aminolevulinic acid-mediated photodynamic therapy resistance in bladder cancer by suppressing ROS accumulation.

作者信息

Tasaka Ryo, Kobatake Kohei, Kohada Yuki, Takemoto Kenshiro, Fukushima Takafumi, Miura Kento, Yamanaka Ryoken, Babasaki Takashi, Sekino Yohei, Kitano Hiroyuki, Goto Keisuke, Goriki Akihiro, Hieda Keisuke, Kaminuma Osamu, Hinata Nobuyuki

机构信息

Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

出版信息

Urol Oncol. 2025 Aug 21. doi: 10.1016/j.urolonc.2025.07.022.

BACKGROUND

Non-muscle invasive bladder cancer (NMIBC) frequently recurs after transurethral resection of bladder tumors, necessitating a novel therapeutic approach. 5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) has emerged as a minimally invasive therapeutic approach; however, its long-term efficacy remains limited, and the mechanisms underlying ALA-PDT resistance are unclear. Lysine-specific demethylase (KDM) 6A, a tumor suppressor frequently mutated in NMIBC, has been implicated in cancer stemness and therapy resistance.

OBJECTIVE

This study aimed to investigate the role of KDM6A deficiency in modulating ALA-PDT efficacy in bladder cancer.

METHODS

KDM6A-knockout (KO) bladder cancer cell lines were established using CRISPR/Cas9-based gene editing. Cancer stemness was evaluated via sphere formation assays and expression of stem cell markers, while the cytotoxic effects of ALA-PDT were assessed through cell viability analysis. Protoporphyrin IX (PpIX) accumulation and reactive oxygen species (ROS) generation were examined using fluorescence microscopy and flow cytometry.

RESULTS

KDM6A-KO cells exhibited significantly increased sphere-forming ability, enhanced stem cell marker expression, and greater resistance to ALA-PDT-induced cytotoxicity. Despite elevated PpIX accumulation in KDM6A-KO cells, ROS levels following ALA-PDT were significantly reduced. A negative correlation between KDM6A expression and ROS-scavenging enzymes expression, particularly SOD2 and GPX1, was confirmed both in public database analyses and in KDM6A-deficient cells.

CONCLUSIONS

These findings indicate that KDM6A deficiency promotes cancer stemness and confers resistance to ALA-PDT in bladder cancer cells by suppressing ROS generation despite increased PpIX levels. This study provides new insights into the role of KDM6A in ALA-PDT resistance and may contribute to developing novel therapeutic and diagnostic strategies for NMIBC.