Biber, G. | bioRxiv Science

bioRxiv2026

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

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.

cancer biology↗

bioRxiv2021

Inhibition of the SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity

Natural Killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator, which dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-{theta} promotes the inhibited SHP-1 "folded" state. Silencing PKC-{theta} maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in-vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.

immunology↗