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- W3197329495 abstract "ABSTRACT The nucleoporin ELYS, encoded by AHCTF1 , is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using a zebrafish model of hepatocellular carcinoma, 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 shrinks tumour burden, while non-hyperplastic tissues are unaffected. We demonstrate that ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly and chromosome segregation, leading to DNA damage and activation of TP53-dependent and independent mechanisms of cell death and cell cycle arrest. This selective vulnerability of cancer cells to mild disruption of Elys function uncovers a novel synthetic lethal interaction between ahctf1 and oncogenic kras that could be exploited therapeutically. Heterozygous expression of both ahctf1 and ranbp2 , or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocked kras G12V -driven hepatocyte hyperplasia, revealing promising avenues for combinatorial treatments." @default.
- W3197329495 created "2021-09-13" @default.
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- W3197329495 date "2021-08-27" @default.
- W3197329495 modified "2023-09-23" @default.
- W3197329495 title "Elys deficiency constrains Kras-driven tumour burden by amplifying oncogenic stress" @default.
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- W3197329495 doi "https://doi.org/10.1101/2021.08.25.457580" @default.
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