ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma
Journal Title
eLife
Publication Type
Research article
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 (kras(G12V)) 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 programme 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 kras(G12V)-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 10 components of the NUP107-160 subcomplex, 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.
Publisher
eLife Sciences Publications
Keywords
Animals; *Carcinoma, Hepatocellular/genetics/pathology; Zebrafish/genetics/metabolism; Nuclear Pore Complex Proteins/genetics/metabolism; Hyperplasia; *Liver Neoplasms/genetics/pathology; Mutation; Proto-Oncogene Proteins p21(ras)/genetics/metabolism; Zebrafish Proteins/genetics/metabolism
Department(s)
Laboratory Research
PubMed ID
36648336
Open Access at Publisher's Site
https://doi.org/10.7554/eLife.73407
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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Last Modified: 2023-06-06 06:45:18

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