Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
Fansuo Geng
Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
Stephen Mieruszynski
Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
Lachlan Whitehead
Department of Medical Biology, University of Melbourne, Parkville, Australia; Centre for Dynamic Imaging, Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Kelly A Smith
Department of Physiology, University of Melbourne, Parkville, Australia; Institute for Molecular Biosciences, University of Queensland, Queensland, Australia
Institute for Molecular Biosciences, University of Queensland, Queensland, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia
Cas Simons
Institute for Molecular Biosciences, University of Queensland, Queensland, Australia; Murdoch Children's Research Institute, Parkville, Australia
Gregory J Baillie
Institute for Molecular Biosciences, University of Queensland, Queensland, Australia
Ramyar Molania
Department of Medical Biology, University of Melbourne, Parkville, Australia; Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Anthony T Papenfuss
Department of Medical Biology, University of Melbourne, Parkville, Australia; Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
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 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 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 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.
