한빛사 논문
Sujin Park,1,7 Dirk Mossmann,1 Qian Chen,2,3 Xueya Wang,2,3 Eva Dazert,1 Marco Colombi,1 Alexander Schmidt,1 Brendan Ryback,4 Charlotte K.Y. Ng,5,6 Luigi M. Terracciano,5,8 Markus H. Heim,2,3 and Michael N. Hall1,9,*
1Biozentrum, University of Basel, 4056 Basel, Switzerland
2Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
3Division of Gastroenterology and Hepatology, Clarunis, University Center for Gastrointestinal and Liver Diseases, 4031 Basel, Switzerland
4Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
5Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland
6Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
7Present address: Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, Republic of Korea
8Present address: Humanitas University, Department of Biomedical Sciences and Department of Pathology, Humanitas Clinical and Research Center, IRCCS, Milan, Italy
9Lead contact
*Correspondence: Michael N Hall
Abstract
Acetyl-coenzyme A (acetyl-CoA) plays an important role in metabolism, gene expression, signaling, and other cellular processes via transfer of its acetyl group to proteins and metabolites. However, the synthesis and usage of acetyl-CoA in disease states such as cancer are poorly characterized. Here, we investigated global acetyl-CoA synthesis and protein acetylation in a mouse model and patient samples of hepatocellular carcinoma (HCC). Unexpectedly, we found that acetyl-CoA levels are decreased in HCC due to transcriptional downregulation of all six acetyl-CoA biosynthesis pathways. This led to hypo-acetylation specifically of non-histone proteins, including many enzymes in metabolic pathways. Importantly, repression of acetyl-CoA synthesis promoted oncogenic dedifferentiation and proliferation. Mechanistically, acetyl-CoA synthesis was repressed by the transcription factors TEAD2 and E2A, previously unknown to control acetyl-CoA synthesis. Knockdown of TEAD2 and E2A restored acetyl-CoA levels and inhibited tumor growth. Our findings causally link transcriptional reprogramming of acetyl-CoA metabolism, dedifferentiation, and cancer.
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