<i>ahctf1</i> and <i>kras</i> mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma.

Abstract

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 cycle arrest. Heterozygous expression of both <i>ahctf1</i> and <i>ranbp2</i> (encoding a second nucleoporin), or treatment of heterozygous <i>ahctf1</i> larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks <i>kras^G12V</i>-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 <i>AHCTF1</i>, 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.