Metabolic alteration is a hallmark of cancer.Dysregulation of methionine metabolism is implicated in human liver cancer.Methionine adenosyltransferase Ⅱα (MAT Ⅱα) is a key enzyme in methionine cycle, catalyzing the production of S-adenosylmethionine (SAM) , key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer.Here we show that P300 acetylates MAT Ⅱα at lysine residue 81 and destabilizes MAT Ⅱα by promoting its ubiquitylation and subsequent proteasomal degradation.