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

Mol Cell. 2022 Nov 17;82(22):4246-4261.e11. doi: 10.1016/j.molcel.2022.10.027.


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.

Keywords: E2A; HCC; TEAD2; acetyl-CoA metabolism; dedifferentiation; hepatocellular carcinoma; protein acetylation; transcriptional reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Hepatocellular* / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Histones / metabolism
  • Liver Neoplasms* / genetics
  • Mice
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Acetyl Coenzyme A
  • Transcription Factors
  • Histones
  • Tead2 protein, mouse
  • DNA-Binding Proteins