科研之友
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摘要
Metabolic alteration is a hallmark of cancer. Dysregulation of methionine metabolism is implicated in human liver cancer. Methionine adenosyltransferase II alpha (MAT II alpha) is a key enzyme in the methionine cycle, catalysing the production of S-adenosylmethionine (SAM), a key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer. Here we show that P300 acetylates MAT II alpha at lysine residue 81 and destabilizes MAT II alpha by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT II alpha by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT II alpha to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT II alpha K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT II alpha regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development.
