Inactivation of citron kinase inhibits medulloblastoma progression by inducing apoptosis and cell senescence.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB consists of surgery followed by irradiation of the whole neuraxis and high-dose multi-agent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting MB growth without disturbing brain development is needed. Citron kinase protein (CITK), encoded by primary microcephaly gene MCPH17, is required for normal proliferation and survival of neural progenitors. Constitutive loss of CITK leads to cytokinesis failure, chromosome instability, and apoptosis in the developing brain, but has limited effects on other tissues. On this basis, we hypothesized that CITK could be an effective target for MB treatment. In MB cell lines DAOY and ONS-76, CITK knockdown increased both cytokinesis failure and DNA damage, impairing proliferation and inducing cell senescence and apoptosis via TP53 or TP73. Similar effects were obtained in the NeuroD-SmoA1 transgenic mouse model, in which CITK deletion increased apoptotic cells and senescence markers such as P21CIP1, P27KIP1, and P16INK4A. Most importantly, CITK deletion decreased tumor growth and increased overall survival in these mice, with no apparent side effects. These results suggest that CITK can be a useful molecular target for MB treatment.

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