Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer

Hong-Bin Yang, Ying-Ying Xu (), Xiang-Ning Zhao, Shao-Wu Zou (), Ye Zhang, Min Zhang, Jin-Tao Li, Feng Ren, Li-Ying Wang and Qun-Ying Lei ()
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Hong-Bin Yang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Ying-Ying Xu: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Xiang-Ning Zhao: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Shao-Wu Zou: Shanghai 10th People’s Hospital, Tong Ji University
Ye Zhang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Min Zhang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Jin-Tao Li: Cancer Metabolism Lab, Institutes of Biomedical Sciences, Fudan University
Feng Ren: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Li-Ying Wang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University
Qun-Ying Lei: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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 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 IIα at lysine residue 81 and destabilizes MAT IIα by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT IIα by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT IIα to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT IIα K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT IIα regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development.

Date: 2015
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DOI: 10.1038/ncomms7973

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