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GLI2 confers ferroptosis resistance in bladder cancer by transcriptionally upregulating PRDX1
Yuyang Yao1,2, Pang Yang2, Shaorui Niu1,2
1Jiangxi Key Laboratory of Oncology, The Third Affiliated Hospital, Jiangxi Medical College, The Central Lab of The First Hospital of Nanchang, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China.
Abstract:
Bladder cancer represents a significant disease burden in men, as it is both highly common and a leading cause of cancer-related deaths. Despite advances in personalized therapies, patient outcomes continue to show considerable variability, and there is an urgent need to explore novel therapeutic targets for this disease. Ferroptosis has recently been implicated in chemotherapy response and proposed as a therapeutic target in various cancers; however, its regulatory mechanism in bladder cancer cells has not been fully elucidated. In this study, we analyzed public data from the GEO database and found that the transcription factor GLI2 was significantly upregulated in bladder cancer compared with normal bladder tissues. Functional assays revealed that GLI2 promotes malignant progression and represses ferroptosis in bladder cancer cells. Mechanistically, RNA sequencing and chromatin immunoprecipitation (ChIP) assays showed that GLI2 transcriptionally regulates the expression of peroxiredoxin 1 (PRDX1), a well-characterized ferroptosis-inhibiting gene. Additionally, rescue assay results indicated that PRDX1 mediates the role of GLI2 in ferroptosis repression and promotes malignant progression of bladder cancer. More importantly, inhibition of GLI2 via siRNA or a small-molecule inhibitor sensitized bladder cancer cells to both PRDX1 inhibitors and cisplatin. Together, these findings delineate a regulatory axis involving GLI2-PRDX1-mediated ferroptosis, provide mechanistic insights into its critical role in driving bladder cancer progression and chemosensitivity, and offer potential therapeutic targets for future clinical intervention.
Insights
The transcription factor GLI2 promotes bladder cancer progression by inhibiting ferroptosis, a cell death pathway. Targeting GLI2 and PRDX1 may offer new therapeutic strategies for bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Bladder cancer is a major health concern, especially for men, with significant mortality.
- Current treatments show variable outcomes, necessitating new therapeutic targets.
- The role of ferroptosis, a regulated cell death, in bladder cancer remains unclear.
Purpose of the Study:
- To investigate the role of the transcription factor GLI2 in bladder cancer.
- To elucidate the mechanism by which GLI2 influences ferroptosis in bladder cancer cells.
- To explore GLI2 and its downstream targets as potential therapeutic strategies.
Main Methods:
- Analysis of public gene expression data (GEO database).
- Functional assays to assess GLI2's role in cancer progression and ferroptosis.
- RNA sequencing and Chromatin Immunoprecipitation (ChIP) assays to identify GLI2 targets.
- Rescue assays and drug sensitivity testing.
Main Results:
- GLI2 is upregulated in bladder cancer and promotes tumor progression while suppressing ferroptosis.
- GLI2 directly regulates the expression of peroxiredoxin 1 (PRDX1), a ferroptosis inhibitor.
- PRDX1 mediates GLI2's effects on ferroptosis and bladder cancer progression.
- Inhibiting GLI2 enhances sensitivity to PRDX1 inhibitors and cisplatin in bladder cancer cells.
Conclusions:
- A novel GLI2-PRDX1 regulatory axis controlling ferroptosis in bladder cancer was identified.
- This axis plays a critical role in bladder cancer progression and chemosensitivity.
- Targeting the GLI2-PRDX1 pathway presents a promising therapeutic avenue for bladder cancer.
