ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma
- Walter and Eliza Hall Institute of Medical Research, Australia
- University of Technology Sydney, Australia
- University of Melbourne, Australia
- Peter MacCallum Cancer Centre, Australia
- Murdoch Children's Research Institute, Australia
- University of Queensland, Australia
- University of Copenhagen, Denmark
- Max Planck Institute for Heart and Lung Research, Germany
- National University of Singapore, Singapore
Abstract
The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional program that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the Liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the ten components of the NUP107-160 sub-complex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.
Data availability
A new RNA sequencing dataset has been deposited in GEO under accession ID GSE220282. Existing datasets analysed during the current study are available in the cBioPortal Cancer Genomics database (http://www.cbioportal.org). All data generated/analysed during this study are included in the Figures and figure supplements and Source Data files are provided for Figures 1-7.
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Molecular characterisation of a mutant kras-driven zebrafish model of hepatocellular carcinomaNCBI Gene Expression Omnibus, GSE220282.
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Liver Hepatocellular Carcinomahttps://www.cbioportal.org/study/summary?id=lihc_tcga_pan_can_atlas_2018.
Article and author information
Author details
Didier YR Stainier
Joan Kathleen Heath
Funding
National Health and Medical Research Council (Project GNT 1024878)
- Joan Kathleen Heath
Australian Government (Graduate Student Training Program)
- Kimberly J Morgan
Ludwig Institute for Cancer Research (Ludwig Member Support Package to Joan Heath)
- Joan Kathleen Heath
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All husbandry and experimental procedures performed on zebrafish followed standard operating procedures and were conducted with the approval of the Animal Ethics Committees of the Walter and Eliza Hall Institute and The University of Melbourne, Parkville, Victoria, Australia. WEHI-AEC approved project 2019.014, project title: Zebrafish disease models and mechanisms.
Copyright
© 2023, Morgan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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