Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN
Abstract FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellu...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07359-9 |
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| author | Yuan Zeng Haoran Jiang Zhoufeng Chen Jun Xu Xiangting Zhang Weimin Cai Xianjie Zeng Peipei Ma Rong lin Huilin Yu Yuanhang He Huiya Ying Ruoru Zhou Xiao Wu Fujun Yu |
| author_facet | Yuan Zeng Haoran Jiang Zhoufeng Chen Jun Xu Xiangting Zhang Weimin Cai Xianjie Zeng Peipei Ma Rong lin Huilin Yu Yuanhang He Huiya Ying Ruoru Zhou Xiao Wu Fujun Yu |
| author_sort | Yuan Zeng |
| collection | DOAJ |
| description | Abstract FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance. |
| format | Article |
| id | doaj-art-f471ac49cbed45debe282c3de56db31d |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-f471ac49cbed45debe282c3de56db31d2025-02-02T12:44:48ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111610.1038/s41419-025-07359-9Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTENYuan Zeng0Haoran Jiang1Zhoufeng Chen2Jun Xu3Xiangting Zhang4Weimin Cai5Xianjie Zeng6Peipei Ma7Rong lin8Huilin Yu9Yuanhang He10Huiya Ying11Ruoru Zhou12Xiao Wu13Fujun Yu14Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Radiation Oncology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversitySchool of Pharmaceutical Science, Fujian Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityThe First Clinical Medical College, Wenzhou Medical UniversityThe First Clinical Medical College, Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical UniversityAbstract FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance.https://doi.org/10.1038/s41419-025-07359-9 |
| spellingShingle | Yuan Zeng Haoran Jiang Zhoufeng Chen Jun Xu Xiangting Zhang Weimin Cai Xianjie Zeng Peipei Ma Rong lin Huilin Yu Yuanhang He Huiya Ying Ruoru Zhou Xiao Wu Fujun Yu Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN Cell Death and Disease |
| title | Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN |
| title_full | Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN |
| title_fullStr | Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN |
| title_full_unstemmed | Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN |
| title_short | Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN |
| title_sort | histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with pten |
| url | https://doi.org/10.1038/s41419-025-07359-9 |
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