CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer

Mou, Haiwei, Eskiocak, Onur, Özler, Kadir A, Gorman, Megan, Yue, Junjiayu, Jin, Ying, Wang, Zhikai, Gao, Ya, Janowitz, Tobias, Meyer, Hannah V, Yu, Tianxiong, Wilkinson, John E, Kucukural, Alper, Ozata, Deniz M, Beyaz, Semir (January 2023) CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer. Journal of Pathology. ISSN 0022-3417

Abstract

CRISPR/Cas9-driven cancer modeling studies are based on disruption of tumor suppressor genes (TSGs) by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of β-catenin induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon skipping events in patients with hepatocellular carcinoma (HCC). Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer. This article is protected by copyright. All rights reserved.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > catenins
Investigative techniques and equipment > CRISPR-Cas9
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon skipping
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
diseases & disorders > cancer > cancer types > liver cancer
CSHL Authors:
Communities: CSHL Cancer Center Program
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Histology Service
CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service
CSHL labs > Beyaz lab
CSHL labs > Fearon lab
CSHL labs > Hammell M. lab
CSHL labs > Janowitz lab
CSHL labs > Meyer Lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 15 January 2023
Date Deposited: 30 Jan 2023 17:52
Last Modified: 29 Apr 2024 19:54
PMCID: PMC10273193
URI: https://repository.cshl.edu/id/eprint/40805

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