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m5C-Modified tRF3b-CysGCA-23 Suppresses Bladder Cancer Malignancy by Repressing H3K18 Lactylation via Stabilizing
Xiaoling Ying1,2, Yapeng Huang3, Jian Huang4,5
1Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Abstract:
The epigenetic modification of transfer RNA (tRNA) and tRNA-derived small RNAs (tsRNAs) is associated with the initiation and development of cancer. However, the biological role of m5C-modified tsRNAs, especially in bladder cancer (BC), and their regulatory mechanisms remain unclear. Here, we identify a novel m5C-modified tsRNA, m5C-tRF3b-CysGCA-23 (mtRC), whose expression is significantly downregulated in both tumor tissues and urine samples of BC patients and is strongly negatively correlated with the malignant progression of bladder cancer. In vitro and in vivo functional experiments reveal that mtRC, but not its unmodified counterpart (tRC), exhibits a tumor-suppressive role. Furthermore, NOP2/Sun RNA methyltransferase 6 (NSUN6) regulates mtRC abundance and suppresses cell proliferation. Mechanistically, mtRC directly binds the oncosuppressor protein RNA-binding motif 4 (RBM4) and improves its stability by preventing RBM4 ubiquitination, thereby upregulating RBM4 protein levels. RBM4 reduces the levels of glycolytic genes and decreases glycolysis, thereby inhibiting histone H3 lysine 18 lactylation (H3K18la). This reduction in H3K18 lactylation attenuates the transcriptional activation of the downstream oncogenes IL1RAP and VASH2, thereby ultimately suppressing tumor malignancy in BC. Together, our results not only underscore the critical role of mtRC in BC but also unravel a novel and coherent regulatory signaling axis-mtRC/RBM4/H3K18la/IL1RAP&VASH2-that orchestrates BC malignancy, suggesting mtRC may serve as a candidate therapeutic target for BC treatment.
Insights
A novel molecule, m5C-modified tsRNA (mtRC), is downregulated in bladder cancer (BC) and acts as a tumor suppressor. It functions via the mtRC/RBM4/H3K18la/IL1RAP&VASH2 axis, offering a potential therapeutic target for BC.
Area of Science:
- Epigenetics
- Molecular Biology
- Oncology
Background:
- Epigenetic modifications of transfer RNA (tRNA) and tRNA-derived small RNAs (tsRNAs) are implicated in cancer development.
- The specific role and regulatory mechanisms of m5C-modified tsRNAs in bladder cancer (BC) remain largely unknown.
Purpose of the Study:
- To identify and characterize a novel m5C-modified tsRNA in bladder cancer.
- To elucidate the biological function and regulatory pathway of this tsRNA in BC progression.
Main Methods:
- Identification and expression analysis of m5C-modified tsRNAs in BC tissues and urine samples.
- In vitro and in vivo functional assays to determine the tumor-suppressive role of the identified tsRNA.
- Mechanistic studies involving RNA-protein binding, ubiquitination, gene expression analysis, and epigenetic modification assays.
Main Results:
- A novel m5C-modified tsRNA, m5C-tRF3b-CysGCA-23 (mtRC), was identified and found to be significantly downregulated in BC.
- mtRC exhibits tumor-suppressive functions, unlike its unmodified counterpart.
- NSUN6 regulates mtRC abundance, which in turn stabilizes RBM4 by inhibiting its ubiquitination.
- The mtRC/RBM4 axis suppresses BC malignancy by reducing glycolysis and H3K18 lactylation, thereby attenuating oncogene expression (IL1RAP and VASH2).
Conclusions:
- mtRC plays a critical tumor-suppressive role in bladder cancer.
- A novel regulatory axis (mtRC/RBM4/H3K18la/IL1RAP&VASH2) controlling BC malignancy has been uncovered.
- mtRC represents a potential diagnostic biomarker and therapeutic target for bladder cancer.
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