ORIGINAL RESEARCH article
Front. Mol. Biosci.
Sec. Molecular Diagnostics and Therapeutics
Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1602700
Epigenetic dysregulation-induced metabolic reprogramming fuels tumor progression in bladder cancer
Provisionally accepted
- 1Department of Urology, Shangyu People's Hospital of Shaoxing, Shaoxing, Zhejiang Province, China
- 2Hangzhou Center for Health Development, Hangzhou, Zhejiang, China, Hangzhou, Jiangsu Province, China
- 3Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- 4Digestive Endoscopy Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
- 5Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
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Bladder cancer remains a significant global health challenge with a high mortality rate despite advancements in treatment modalities. Metabolic alterations serve as crucial contributors to cancer progression, particularly influencing tumor aggressiveness and patient outcomes. Here, we employed a metabolism-targeted approach to identify the metabolic hubs of disease progression and clinical outcomes in bladder cancer patients. Differential expression and survival analyses identified 105 metabolic genes with expression patterns that correlated with tumor aggressiveness and clinical outcomes in bladder cancer patients. Subsequent network construction and random walk analysis refined this list to a seven-gene metabolic signature (Metab-GS), comprising both oncogenic (ALDH1B1, ALDH1L2, CHSY1, CSGALNACT2, GPX8) and tumor suppressors (FBP1, HPGD) hubs. In addition, upstream analysis identified epigenetic modifications, particularly DNA hypermethylation of tumor suppressor metabolic hubs and reduced USF2-NuRD complex activity-driven increased expression of oncogenic metabolic hubs, contributing to glycolytic shift and extracellular matrix remodeling, and establishing an inflammatory tumor microenvironment. Lastly, validation of our findings in independent multiple GEO datasets confirmed that high Metab-GS scores are associated with tumor aggressiveness and progression, advanced disease stage, metastatic spread, disease recurrence, and poor overall and cancer-specific survival in bladder cancer patients. These findings underscore the potential of targeting the epigenetic dysregulation-induced metabolic reprogramming as a therapeutic strategy for aggressive bladder cancer.
Keywords: Bladder cancer, metabolic reprogramming, Tumor aggressiveness, Inflammation, DNA Methylation, USF2, NuRD complex
Received: 30 Mar 2025; Accepted: 13 Jun 2025.
Copyright: © 2025 Zhang, Fan, Xu, Han, Yu, Yang, Chen and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Bicheng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
Yanling Chen, Digestive Endoscopy Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
Shaolin Zhang, Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui Province, China
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