Programmable base editing of mutated TERT promoter inhibits brain tumour growth.
Xinjian LiXu QianBin WangYan XiaYanhua ZhengLinyong DuDaqian XuDongming XingRonald A DePinhoZhimin LuPublished in: Nature cell biology (2020)
Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications1-4. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma5-8. Correction of the -124C>T TERT promoter mutation to -124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.
Keyphrases
- crispr cas
- transcription factor
- genome editing
- dna methylation
- genome wide
- papillary thyroid
- gene expression
- dna binding
- squamous cell
- genome wide identification
- copy number
- cystic fibrosis
- signaling pathway
- bone marrow
- antimicrobial resistance
- climate change
- dna damage
- risk assessment
- staphylococcus aureus
- genetic diversity
- candida albicans