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

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.