biostudies-literatureMorgan KJNational Health and Medical Research CouncilAustralian GovernmentLudwig Institute for Cancer ResearchNovo Nordisk Fondene73407https://www.ebi.ac.uk/biostudies/studies/S-EPMC9897728biostudies-literatureUnknown12The nucleoporin (NUP) ELYS, encoded by <i>AHCTF1</i>, 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 <i>kras</i> transgene (<i>kras^G12V</i>) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing <i>ahctf1</i> gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, <i>ahctf1</i> 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 eLife<i>ahctf1</i> and <i>kras</i> mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma.PMC9897728Ludwig Member Support PackageNNF21SA0073733Project GNT 1024878Graduate Student Training ProgramPapenfuss ATBaillie GJWhitehead LHogan BMHeath JKGong ZMieruszynski SStainier DYRMorgan KJHall TEOber EAGeng FSmith KADoggett KSimons CMolania Rfalse<i>ahctf1</i> and <i>kras</i> mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma.The nucleoporin (NUP) ELYS, encoded by <i>AHCTF1</i>, 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 <i>kras</i> transgene (<i>kras^G12V</i>) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing <i>ahctf1</i> gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, <i>ahctf1</i> 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 2023-01-01T00:00:00Z2023 Jan2026-05-28T08:13:39.567Z2024-11-07T06:03:08.203ZS-EPMC98977283664833610.7554/eLife.73407