Base editing of the mutated TERT promoter inhibits liver tumor growth.

Abstract

BACKGROUND AND AIMS:

Base editing has shown great potential for treating human diseases with mutated genes. However, its potential for treating hepatocarcinoma (HCC) has not yet explored.

APPROACH AND RESULTS:

We employed adenine base editors (ABEs) to correct a 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 ETS (ETS/TCF) transcription factor family, including ETS1 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.

• Authors: Gaoxiang Zhao, Qingxia Ma, Huang Yang, Hongfei Jiang, Qianqian Xu, Shudi Luo, Zhaoyuan Meng, Juanjuan Liu, Lei Zhu, Qian Lin, Min Li, Jing Fang, Leina Ma, Wensheng Qiu, Zhengwei Mao, Zhimin Lu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) (Nov 28 2023) ISSN: 1527-3350 [Electronic] United States
• PMID: 38016019 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 American Association for the Study of Liver Diseases.