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N6-methyladenosine-modified SRD5A3, identified by IGF2BP3, sustains cisplatin resistance in bladder cancer
Kai Liao1, Jing Li2, Caixian He3
1Department of Radiotherapy, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, No. 78 Hengzhigang, Yuexiu District, Guangzhou, 510095, China. coolio620@163.com.
Abstract:
Resistance to cisplatin-based chemotherapy limits the clinical benefit to some bladder cancer patients, and understanding the epigenetic regulation mechanism of cisplatin (CDDP) resistance in bladder cancer from the perspective of N6-methyladenosine (m6A) modification may optimize CDDP-based treatments. The study identified SRD5A3 as an oncogene for bladder cancer and stabilized by a m6A reader, IGF2BP3, to sustain CDDP resistance. Our results revealed that the expression of SRD5A3 was elevated in human bladder cancer tissues and cell lines, and this elevation was more evident in CDDP-resistant T24 and 5637 cells. Results of CCK-8 assay, colony formation assay, EdU staining, and flow cytometric analysis revealed that SRD5A3 knockdown and IGF2BP3 knockdown reduced cell proliferation and prevented chemoresistance in CDDP-resistant T24 and 5637 cells. Results of methylated RNA immunoprecipitation-PCR, RNA immunoprecipitation assay, and luciferase reporter assay showed IGF2BP3 recognized the SRD5A3 m6A modification and stabilized its mRNA. Nude mice implanted subcutaneously with CDDP-resistant T24 cells were injected intraperitoneally with CDDP (2 mg/kg) every 3 days for 35 days and the results demonstrated that SRD5A3 knockdown and IGF2BP3 knockdown effectively inhibited the tumor growth in subcutaneous implantation model. Collectively, the study unveils that IGF2BP3-mediated SRD5A3 m6A modification facilitates bladder cancer progression and induces CDDP resistance, providing rational therapeutic targets for bladder cancer patients.
Insights
This study reveals how N6-methyladenosine (m6A) modification, specifically involving IGF2BP3 and SRD5A3, drives cisplatin resistance in bladder cancer. Targeting this pathway offers potential new treatments for patients with bladder cancer.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Cisplatin resistance limits bladder cancer treatment efficacy.
- N6-methyladenosine (m6A) modification is an emerging epigenetic mechanism in cancer.
- Understanding m6A's role in cisplatin resistance is crucial for therapeutic optimization.
Purpose of the Study:
- To investigate the role of m6A modification in cisplatin resistance in bladder cancer.
- To identify key molecules involved in this epigenetic regulation.
- To explore potential therapeutic targets for overcoming cisplatin resistance.
Main Methods:
- Analysis of SRD5A3 and IGF2BP3 expression in bladder cancer tissues and cell lines.
- Cell proliferation and chemoresistance assays (CCK-8, colony formation, EdU, flow cytometry).
- Molecular techniques including m6A immunoprecipitation, RNA immunoprecipitation, and luciferase reporter assays.
- In vivo studies using a nude mouse xenograft model.
Main Results:
- SRD5A3 expression is elevated in bladder cancer, particularly in cisplatin-resistant cells.
- IGF2BP3 stabilizes SRD5A3 mRNA via m6A modification, promoting cisplatin resistance.
- Knockdown of SRD5A3 or IGF2BP3 reduced cell proliferation and reversed chemoresistance.
- In vivo, SRD5A3 and IGF2BP3 knockdown inhibited tumor growth in cisplatin-resistant models.
Conclusions:
- IGF2BP3-mediated m6A modification of SRD5A3 promotes bladder cancer progression and cisplatin resistance.
- SRD5A3 and IGF2BP3 represent potential therapeutic targets for overcoming cisplatin resistance in bladder cancer.
- This study provides insights into the epigenetic mechanisms underlying chemoresistance.
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