Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression
Breast cancer (BC) has become the leading cause of global cancer incidence. Despite therapeutic advances, a critical unmet need persists for identifying novel therapeutic targets. Our integrated bioinformatics analysis identified DTL, a component of the Cullin-RING ligase (CRL) E3 ubiquitin ligase f...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1583752/full |
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| author | Yuhao Liu Jinting Li Yiren Cao Mengzhu Lv |
| author_facet | Yuhao Liu Jinting Li Yiren Cao Mengzhu Lv |
| author_sort | Yuhao Liu |
| collection | DOAJ |
| description | Breast cancer (BC) has become the leading cause of global cancer incidence. Despite therapeutic advances, a critical unmet need persists for identifying novel therapeutic targets. Our integrated bioinformatics analysis identified DTL, a component of the Cullin-RING ligase (CRL) E3 ubiquitin ligase family, as significantly upregulated in BC tissues. This upregulation correlated with poor patient prognosis, cancer stemness, and metabolic reprogramming, which was driven by genetic alterations such as gene amplification and reduced promoter methylation. Functional studies demonstrated that DTL promoted breast cancer cell proliferation and migration in vitro through glycolysis remodeling. Mechanistically, DTL positively regulated key glycolytic enzymes (HK2, ENO1, PKM2, and LDHA) independently of its canonical ubiquitin ligase activity and directly interacted with LDHA. Notably, exogenous L-lactate directly enhanced BC tumor growth and metastasis. Collectively, our findings reveal a non-canonical mechanism whereby DTL drives glycolysis to generate the oncometabolite L-lactate, which directly sustains breast cancer malignancy independent of protein degradation. The strong association between DTL upregulation and adverse clinical outcomes, coupled with its multifaceted regulatory roles in tumor biology, highlighting its therapeutic potential as a novel target in BC. |
| format | Article |
| id | doaj-art-8cb07771ed654dfa9b502edf49bd1727 |
| institution | OA Journals |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-8cb07771ed654dfa9b502edf49bd17272025-08-20T02:35:16ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-05-011510.3389/fonc.2025.15837521583752Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progressionYuhao Liu0Jinting Li1Yiren Cao2Mengzhu Lv3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, ChinaBreast cancer (BC) has become the leading cause of global cancer incidence. Despite therapeutic advances, a critical unmet need persists for identifying novel therapeutic targets. Our integrated bioinformatics analysis identified DTL, a component of the Cullin-RING ligase (CRL) E3 ubiquitin ligase family, as significantly upregulated in BC tissues. This upregulation correlated with poor patient prognosis, cancer stemness, and metabolic reprogramming, which was driven by genetic alterations such as gene amplification and reduced promoter methylation. Functional studies demonstrated that DTL promoted breast cancer cell proliferation and migration in vitro through glycolysis remodeling. Mechanistically, DTL positively regulated key glycolytic enzymes (HK2, ENO1, PKM2, and LDHA) independently of its canonical ubiquitin ligase activity and directly interacted with LDHA. Notably, exogenous L-lactate directly enhanced BC tumor growth and metastasis. Collectively, our findings reveal a non-canonical mechanism whereby DTL drives glycolysis to generate the oncometabolite L-lactate, which directly sustains breast cancer malignancy independent of protein degradation. The strong association between DTL upregulation and adverse clinical outcomes, coupled with its multifaceted regulatory roles in tumor biology, highlighting its therapeutic potential as a novel target in BC.https://www.frontiersin.org/articles/10.3389/fonc.2025.1583752/fullDTLglycolysisL-lactatebreast cancerprogression |
| spellingShingle | Yuhao Liu Jinting Li Yiren Cao Mengzhu Lv Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression Frontiers in Oncology DTL glycolysis L-lactate breast cancer progression |
| title | Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression |
| title_full | Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression |
| title_fullStr | Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression |
| title_full_unstemmed | Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression |
| title_short | Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression |
| title_sort | rewired glycolysis by dtl accelerates oncometabolite l lactate generation to promote breast cancer progression |
| topic | DTL glycolysis L-lactate breast cancer progression |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1583752/full |
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