tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer
Background: Enhanced glycolysis contributes to the chemotherapy resistance of colorectal cancer (CRC). However, whether tRNA-derived small RNAs (tsRNAs) regulate CRC oxaliplatin sensitivity through glycolysis-mediated histone lactylation remains unclear. Methods: By analyzing RNA-seq data from CRC s...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001585 |
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| author | Zhengbo Chen Yiyang Zhang Fang Yan Gang Zhao Yan Wang |
| author_facet | Zhengbo Chen Yiyang Zhang Fang Yan Gang Zhao Yan Wang |
| author_sort | Zhengbo Chen |
| collection | DOAJ |
| description | Background: Enhanced glycolysis contributes to the chemotherapy resistance of colorectal cancer (CRC). However, whether tRNA-derived small RNAs (tsRNAs) regulate CRC oxaliplatin sensitivity through glycolysis-mediated histone lactylation remains unclear. Methods: By analyzing RNA-seq data from CRC samples in the TCGA database, we identified a glucose metabolism-related tsRNA. Overexpression of tsRNA-08614 was investigated to explore its impact on CRC sensitivity to oxaliplatin. The targeting gene of tsRNA-08614 was validated through a dual-luciferase reporter assay. The specific molecular mechanism of tsRNA-08614 regulating CRC oxaliplatin sensitivity was further revealed by ChIP-seq and RNA-seq. Results: We found a down-regulated tsRNA-08614 targeted glycolysis-related gene, which was associated with chemotherapy resistance. Overexpression of tsRNA-08614 promoted oxaliplatin sensitivity of CRC cells. tsRNA-08614 inhibited the expression of the target gene ALDH1A3 and reduced glycolysis, whereas the glycolytic inducer reversed the enhanced sensitivity caused by tsRNA-08614. Interference of tsRNA-08614 increased H3K18la and pan-Kla levels, while the lactate inhibitor partially suppressed these effects. Furthermore, overexpression of tsRNA-08614 reprogrammed the transcription of genes mediated by histone lactylation modification, with EFHD2 showing the most significant differential expression. EFHD2 inhibited the sensitivity of CRC cells to oxaliplatin by upregulating CMPK2 and enhancing mitochondrial function. Finally, we demonstrated that tsRNA-08614 enhanced sensitivity to oxaliplatin in CRC by reducing histone lactylation levels in vivo. Conclusion: tsRNA-08614 regulates ALDH1A3 to inhibit glycolysis and histone lactylation modification, thereby suppressing the transcriptional activity of EFHD2 and ultimately promoting the sensitivity of CRC to oxaliplatin. These findings suggest that tsRNA-08614 may represent a novel molecular target to combat oxaliplatin resistance in CRC chemotherapy. |
| format | Article |
| id | doaj-art-ac6418444af54aca9d89d9f769dc84f9 |
| institution | OA Journals |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-ac6418444af54aca9d89d9f769dc84f92025-08-20T02:06:20ZengElsevierTranslational Oncology1936-52332025-08-015810242710.1016/j.tranon.2025.102427tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancerZhengbo Chen0Yiyang Zhang1Fang Yan2Gang Zhao3Yan Wang4Department of Vascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, ChinaDepartment of Endoscopy, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaDepartment of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaDepartment of Vascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Corresponding authors.Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding authors.Background: Enhanced glycolysis contributes to the chemotherapy resistance of colorectal cancer (CRC). However, whether tRNA-derived small RNAs (tsRNAs) regulate CRC oxaliplatin sensitivity through glycolysis-mediated histone lactylation remains unclear. Methods: By analyzing RNA-seq data from CRC samples in the TCGA database, we identified a glucose metabolism-related tsRNA. Overexpression of tsRNA-08614 was investigated to explore its impact on CRC sensitivity to oxaliplatin. The targeting gene of tsRNA-08614 was validated through a dual-luciferase reporter assay. The specific molecular mechanism of tsRNA-08614 regulating CRC oxaliplatin sensitivity was further revealed by ChIP-seq and RNA-seq. Results: We found a down-regulated tsRNA-08614 targeted glycolysis-related gene, which was associated with chemotherapy resistance. Overexpression of tsRNA-08614 promoted oxaliplatin sensitivity of CRC cells. tsRNA-08614 inhibited the expression of the target gene ALDH1A3 and reduced glycolysis, whereas the glycolytic inducer reversed the enhanced sensitivity caused by tsRNA-08614. Interference of tsRNA-08614 increased H3K18la and pan-Kla levels, while the lactate inhibitor partially suppressed these effects. Furthermore, overexpression of tsRNA-08614 reprogrammed the transcription of genes mediated by histone lactylation modification, with EFHD2 showing the most significant differential expression. EFHD2 inhibited the sensitivity of CRC cells to oxaliplatin by upregulating CMPK2 and enhancing mitochondrial function. Finally, we demonstrated that tsRNA-08614 enhanced sensitivity to oxaliplatin in CRC by reducing histone lactylation levels in vivo. Conclusion: tsRNA-08614 regulates ALDH1A3 to inhibit glycolysis and histone lactylation modification, thereby suppressing the transcriptional activity of EFHD2 and ultimately promoting the sensitivity of CRC to oxaliplatin. These findings suggest that tsRNA-08614 may represent a novel molecular target to combat oxaliplatin resistance in CRC chemotherapy.http://www.sciencedirect.com/science/article/pii/S1936523325001585tsRNAGlycolysisHistone lactylationColorectal cancer |
| spellingShingle | Zhengbo Chen Yiyang Zhang Fang Yan Gang Zhao Yan Wang tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer Translational Oncology tsRNA Glycolysis Histone lactylation Colorectal cancer |
| title | tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer |
| title_full | tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer |
| title_fullStr | tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer |
| title_full_unstemmed | tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer |
| title_short | tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer |
| title_sort | tsrna 08614 inhibits glycolysis and histone lactylation by aldh1a3 to confer oxaliplatin sensitivity in colorectal cancer |
| topic | tsRNA Glycolysis Histone lactylation Colorectal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001585 |
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