2. Academic Validation
  3. Melatonin suppresses glycolysis and coordinately disrupts DNA repair via targeting the YAP1-NAMPT signaling in breast cancer

Melatonin suppresses glycolysis and coordinately disrupts DNA repair via targeting the YAP1-NAMPT signaling in breast cancer

  • Chem Biol Interact. 2026 Feb 11:425:111900. doi: 10.1016/j.cbi.2026.111900.
Yi-Wen Lai 1,  Cheng-Ying Chu 2,  Zei-Wei Liu 1,  Hsin-Ying Lu 3,  Chi-Ching Lee 4,  Mei-Hsiang Lin 5,  Cheng-Wei Lin 6
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
  • 2 CRISPR Gene Targeting Core Lab, Taipei Medical University, Taipei, 110, Taiwan.
  • 3 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taiwan.
  • 4 Department of Food Engineering, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Istanbul, 343, Türkiye; Department of Food Technology and Nutrition, Faculty of Technologies, Klaipėdos valstybinė kolegija, Higher Education Institution, Lithuania.
  • 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan. Electronic address: [email protected].
  • 6 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. Electronic address: [email protected].
PMID: 41485639 DOI: 10.1016/j.cbi.2026.111900
Abstract

Triple-negative breast Cancer (TNBC) is characterized by aggressive behavior and high recurrence rates, contributing to poor prognoses of TNBC patients. However, the lack of appropriate molecular targets limits the effectiveness of current antineoplastic therapies. Therefore, effective therapeutic strategies are urgently needed. Melatonin (N-acetyl-5-methoxytryptamine) has shown a broad spectrum of Anticancer activities, but its potential for treating TNBC remains elusive. In this study, we discovered that melatonin suppressed the growth and invasiveness of TNBC cells through downregulating glycolytic capacity in association with inhibition of Yes-associated protein 1 (YAP1) signaling. Notably, melatonin suppressed expression of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme participated in nicotinamide adenine dinucleotide (NAD) turnover and contributes to protein poly(ADP)-ribosylation (PARylation). As a result, melatonin potentiated DNA damage and elevated Apoptosis. Furthermore, it is found that melatonin suppressed NAMPT expression via inhibition of YAP1. Moreover, downregulation of glycolysis decreased protein PARylation levels and increased DNA damage accumulation, suggesting that melatonin suppresses the crosstalk between glycolysis and DNA repair signaling. Combined treatment with melatonin and Olaparib, an inhibitor of the major conductor of protein PARylation, poly(ADP-ribose) polymerase (PARP), showed additive inhibitory effects on breast Cancer proliferation compared to their single treatment. These findings demonstrated that melatonin may be a promising agent for targeting YAP1-mediated glycolysis and DNA repair in breast Cancer for enhancing the therapeutic efficacy of Olaparib in TNBC patients.

Keywords

DNA repair; Glycolysis; Melatonin; NAMPT; Olaparib; TNBC; Yes-associated protein 1 (YAP1).

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