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ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Metabolism
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1583752
Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression
Provisionally accepted- Beijing Cancer Hospital, Peking University, Beijing, China
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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, immunosuppression, cancer stemness, and metabolic reprogramming, which were driven by genetic alterations such as gene amplification and reduced promoter methylation. Functional studies demonstrated that DTL promotes 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, highlights its therapeutic potential as a novel target in BC.
Keywords: DTL, Glycolysis, L-lactate, breast cancer, progression
Received: 26 Feb 2025; Accepted: 11 Apr 2025.
Copyright: © 2025 Lv, Liu, Li and Cao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mengzhu Lv, Beijing Cancer Hospital, Peking University, Beijing, China
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