Exogenous pyruvate represses histone gene expression to inhibit cancer cell proliferation via the NAMPT-NAD + -SIRT1 pathway

Pyruvate is a glycolytic metabolite used for energy production and macromolecule biosynthesis. However, little is known about its potential functions in tumorigenesis. Here,we report that exogenous pyruvate inhibits the proliferation of different types of cancer cells. This inhibitory effect of pyruvate on cell growth is attributed to its function as a signal molecule to repress histone gene expression, which leads to less compact chromatin structure and misregulation of genome-wide gene expression. Pyruvate represses histone gene expression by inducing the expression of NAD + biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), which increases NAD + levels and NAD + /NADH ratio. This increase activates the histone deacetylase activity of SIRT1. Chromatin immunoprecipitation analysis indicates that pyruvate enhances SIRT1 binding at histone gene promoters where it reduces histone acetylation. Although pyruvate delays cell entry into S phase, pyruvate represses histone gene expression independent of cell cycle progression. Moreover, we find that administration of pyruvate significantly reduces histone expression and retards tumor growth in xenograft mice without significant side effects. Using tissues from cervical cancer patients, we find intracellular pyruvate concentrations inversely correlate with histone protein levels. Together, we uncover a previously unknown function of pyruvate in histone gene expression and characterize pyruvate as a potential anti-cancer agent. RNA Sequencing Analysis between no treatment and pyruvate treatment in HeLa cells.