Nicotinylation is a histone mark generated from the nicotinic acid metabolite nicotinyl-CoA

Protein post-translational modifications (PTMs) are crucial for cancer growth and metastasis. Vitamin B3, a key precursor of NAD + and NADP+, however its epigenetic functions in physiology and disease remain unclear. Herein we report a nicotinic acid (NA), a component of vitamin B3, induces a histone PTM, lysine nicotinylation (Knic), and demonstrate 17 Knic site across core histones in cells. Tandem mass spectrometry and stable isotope tracing revealed that NA-derived nicotinyl-CoA, catalysed by ACSS2, enhances histone Knic in vivo and in vitro . Analysis of chromatin accessibility revealed that histone Knic downregulates chromatin accessibility and therefore inhibits gene expression, for instance, restrain the binding of transcription factor HOXB9 to the promoter of oncogene PPFIA1. PPFIA1 level is correlated with malignancy and poor prognosis of hepatocellular carcinoma. These findings suggest that vitamin B3 supplementation may affects the chromatin accessibility depending on its composition. Collectively, we propose that NA induces histone Knic, a histone mark controlling gene expression.