The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression

Sep 24, 2026

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Aberrant glucose metabolism is a characteristic of bladder cancer, and hyperglycemia is associated with disease development and progression, yet the mechanism linking high glucose to tumor aggressiveness remains incompletely understood. This study focuses on N6-methyladenosine (m6A) signaling, showing that the m6A reader YTHDC1 is regulated by high-glucose conditions, is downregulated in bladder cancer tissues, and correlates with prognosis. YTHDC1 suppresses malignant progression and glycolysis via an m6A-dependent pathway mediated by GLUT3. Further, GLUT3 destabilizes YTHDC1 through RNF183 upregulation, defining a YTHDC1/GLUT3/RNF183 positive feedback loop relevant to hyperglycemic tumor biology.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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INTRODUCTION

Bladder cancer overview and therapies

Hyperglycemia and altered glucose metabolism in cancer

m6A modification and the role of YTHDC1

[www.nature.com/emm](www.nature.com/emm) ARTICLE OPEN The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression Bin Yan1,2,5, Xurui Li1,2,5, Mou Peng1,2, Yali Zuo 1, Yinhuai Wang1, Pian Liu 3 ✉, Weigang Ren4 ✉ and Xin Jin 1,2 ✉ © The Author(s) 2023 | | | | | --- | --- | --- | | | Aberrant glucose metabolism is a characteristic of bladder cancer. Hyperglycemia contributes to the development and progression of bladder cancer. However, the underlying mechanism by which hyperglycemia promotes the aggressiveness of cancers, especially bladder cancer, is still incompletely understood. N6-methyladenosine (m6A) modiﬁcation is a kind of methylation modiﬁcation occurring at the N6 position of adenosine that is important for the pathogenesis of urological tumors. Recently, it was found that the m6A reader YTHDC1 is regulated by high-glucose conditions. In our study, we revealed that YTHDC1 is not only regulated by high-glucose conditions but is also downregulated in bladder cancer tissue and associated with the prognosis of cancer. We also showed that YTHDC1 suppresses the malignant progression of and the glycolytic process in bladder cancer cells in an
m6A-dependent manner and determined that this effect is partially mediated by GLUT3 . Moreover, GLUT3 was found to destabilize YTHDC1 by upregulating RNF183 expression. In summary, we identiﬁed a novel YTHDC1/GLUT3/RNF183 feedback loop that regulates disease progression and glucose metabolism in bladder cancer. Collectively, this study provides new insight regarding the pathogenesis of bladder cancer under hyperglycemic conditions and might reveal ideal candidates for the development of drugs | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | for bladder cancer. | | | | | Experimental & Molecular Medicine (2023) 55:1145–1158; [https://doi.org/10.1038/s12276-023-00997-z](https://doi.org/10.1038/s12276-023-00997-z) | | | | | | INTRODUCTION Bladder cancer is the most common malignancy of the urinary system1,2. Bladder cancer is the ﬁfth most common cancer3, and nearly 170,000 patients die of this disease worldwide each year3–5. For muscle-invasive and advanced bladder cancer, platinumbased chemotherapy has been considered the standard systemic therapy over the past 40 years5. Due to the high mutation burden of bladder cancer, immunotherapy has been used to treat bladder cancer and has substantially improved the prognosis of patients in recent years6. However, studies exploring the molecular mechanism of advanced bladder cancer are also needed for the development of new therapeutic strategies. Aberrant glucose metabolism is one of the characteristics of malignant tumors7. In 1885, it was ﬁrst reported that patients with cancer exhibited high blood glucose concentrations. Later, Warburg et al. noted that cancer tissues maintained a higher glucose utilization rate than normal tissues8. High blood glucose, or hyperglycemia, is usually caused by stress, diabetes mellitus, inﬂammation, or some kinds of drugs9–11. Among these causes, diabetes mellitus is the most common reason for long-term elevation of the plasma glucose concentration. Large cohort studies have demonstrated that diabetes mellitus-induced hyperglycemia is crucial for the tumorigenesis of solid tumors, such as liver12, pancreatic13, and bladder14, 15 cancers. Lattermann et al. analyzed glucose metabolism in patients with bladder cancer. They found that the plasma concentration of glucose was elevated in patients with bladder cancer due to the lower rate of glucose clearance16. Moreover, it has been mentioned that hyperglycemia contributes to the development and progression of bladder cancer in diabetic patients. High glucose-mediated promotion of metastasis leads to death in patients with bladder cancer and diabetes17. Mechanistically, the excessive glucose supply availa

FAQs

Why is hyperglycemia considered important in bladder cancer progression?

Hyperglycemia is linked to the development and progression of bladder cancer, providing excess glucose and supporting high glycolysis rates that create a favorable microenvironment for malignant behavior.

What role does YTHDC1 play in bladder cancer under high-glucose conditions?

YTHDC1 is regulated by high-glucose conditions, is downregulated in bladder cancer tissues, and is associated with prognosis. It suppresses malignant progression and glycolysis in an m6A-dependent manner.

How are GLUT3 and RNF183 connected to the YTHDC1 pathway?

GLUT3 mediates YTHDC1’s effects and destabilizes YTHDC1 by upregulating RNF183, forming a YTHDC1/GLUT3/RNF183 feedback loop that modulates glucose metabolism and disease progression.

Sep 24, 2026

Uploaded by Connor