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Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis

Park, Sujin and Mossmann, Dirk and Chen, Qian and Wang, Xueya and Dazert, Eva and Colombi, Marco and Schmidt, Alexander and Ryback, Brendan and Ng, Charlotte K. Y. and Terracciano, Luigi M. and Heim, Markus H. and Hall, Michael N.. (2022) Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis. Molecular Cell, 82 (22). pp. 4246-4261.e11.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1097-2765
e-ISSN:1097-4164
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:18 Jan 2023 04:11
Deposited On:17 Jan 2023 10:37

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