FTO regulates centrosome function and mitotic fidelity in cancers with chromosome instability (CIN)

2026 · doi:10.64898/2026.03.22.713449
preprint OA: closed
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Abstract

Centrosomes are essential for spindle assembly and accurate chromosome segregation during mitosis. We found that the RNA demethylase FTO localizes to centrosomes in both human and mouse cells. Disruption of FTO function through a newly developed small-molecule inhibitor impaired spindle organization and centrosome function. This was evidenced by chromosome misalignment during mitosis, prometaphase arrest, followed by mitotic slippage or apoptosis. Mechanistically, we found that FTO is essential for intact localization of NuMA and KIFC1 proteins required for chromosome localization during mitosis. Importantly, cancers characterized by chromosomal instability (CIN) showed increased sensitivity to FTO inhibition compared to normal cells. These findings underscore FTO as a promising therapeutic target in CIN cancer subsets.
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Abstract Centrosomes are essential for spindle assembly and accurate chromosome segregation during mitosis. We found that the RNA demethylase FTO localizes to centrosomes in both human and mouse cells. Disruption of FTO function through a newly developed small-molecule inhibitor impaired spindle organization and centrosome function. This was evidenced by chromosome misalignment during mitosis, prometaphase arrest, followed by mitotic slippage or apoptosis. Mechanistically, we found that FTO is essential for intact localization of NuMA and KIFC1 proteins required for chromosome localization during mitosis. Importantly, cancers characterized by chromosomal instability (CIN) showed increased sensitivity to FTO inhibition compared to normal cells. These findings underscore FTO as a promising therapeutic target in CIN cancer subsets. Competing Interest Statement L.C.A., Y.M., G.B., D.K., M.H., R.E., and A.P. were employees of RNAble Ltd. and may hold equity in the company. R.K. and A.M. are Co-Founders of RNAble Ltd. and hold equity in the company. A.M. serves as Chief Scientific Officer of RNAble Ltd. Footnotes A typo in Figure 7 has been corrected.

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last seen: 2026-05-20T01:45:00.602351+00:00