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 > 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 diseases & disorders > cancer > cancer types > liver cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab CSHL labs > Fearon lab CSHL labs > Hammell M. lab CSHL labs > Janowitz lab CSHL labs > Meyer Lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 15 January 2023 |
| Date Deposited: | 30 Jan 2023 17:52 |
| Last Modified: | 30 Jan 2023 17:52 |
| URI: | https://repository.cshl.edu/id/eprint/40805 |
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