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. Hall^1,9,*

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

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.