Base editing of the mutated TERT promoter inhibits liver tumor growth

Hepatology. 2024 Jun 1;79(6):1310-1323. doi: 10.1097/HEP.0000000000000700. Epub 2023 Nov 28.


Background and aims: Base editing has shown great potential for treating human diseases with mutated genes. However, its potential for treating HCC has not yet been explored.

Approach and results: We employed adenine base editors (ABEs) to correct a telomerase reverse transcriptase ( TERT ) promoter mutation, which frequently occurs in various human cancers, including HCC. The mutated TERT promoter -124 C>T is corrected to -124 C by a single guide (sg) RNA-guided and deactivated Campylobacter jejuni Cas9 (CjCas9)-fused adenine base editor (CjABE). This edit impairs the binding of the E-twenty six/ternary complex factor transcription factor family, including E-twenty six-1 and GABPA, to the TERT promoter, leading to suppressed TERT promoter and telomerase activity, decreased TERT expression and cell proliferation, and increased cell senescence. Importantly, injection of adeno-associated viruses expressing sgRNA-guided CjABE or employment of lipid nanoparticle-mediated delivery of CjABE mRNA and sgRNA inhibits the growth of liver tumors harboring TERT promoter mutations.

Conclusions: These findings demonstrate that a sgRNA-guided CjABE efficiently converts the mutated TERT promoter -124 C>T to -124 C in HCC cells and underscore the potential to treat HCC by the base editing-mediated correction of TERT promoter mutations.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Editing* / methods
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / therapy
  • Mice
  • Mutation
  • Promoter Regions, Genetic*
  • Telomerase* / genetics
  • Telomerase* / metabolism


  • TERT protein, human