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:	Mou, Haiwei Eskiocak, Onur Jin, Ying Wang, Zhikai Janowitz, Tobias Meyer, Hannah V. Beyaz, Semir Ozler, Kadir Gorman, Megan Yue, Junjiayu Gao, Ya
Communities:	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 CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance 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
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	15 January 2023
Date Deposited:	30 Jan 2023 17:52
Last Modified:	09 Feb 2024 15:35
PMCID:	PMC10273193
URI:	https://repository.cshl.edu/id/eprint/40805

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