Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer.
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.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Hong-Bin
HB
Yang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Ying-Ying
YY
Xu
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Department of Hepatopancreatobiliary Surgery, Shanghai 10th People's Hospital, Tong Ji University, Shanghai 200072, China.
Xiang-Ning
XN
Zhao
Department of Hepatopancreatobiliary Surgery, Shanghai 10th People's Hospital, Tong Ji University, Shanghai 200072, China.
Shao-Wu
SW
Zou
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Ye
Y
Zhang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Min
M
Zhang
Cancer Metabolism Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Jin-Tao
JT
Li
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Feng
F
Ren
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Li-Ying
LY
Wang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Cancer Metabolism Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.|Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiaotong University, Shanghai 200025, China.
Qun-Ying
QY
Lei
D000107:Acetylation; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D054875:Ubiquitination; D000099186:Histone Deacetylase 3
D050881:E1A-Associated p300 Protein; D005492:Folic Acid; D006655:Histone Deacetylases; D008716:Methionine Adenosyltransferase; D000099186:Histone Deacetylase 3; C527161:MAT2A protein, human