Loss of DIAPH3 accelerates glioma genesis in mice

Abstract DIAPH3 is a master regulator of the cytoskeleton with key roles in cell division. In the mouse brain, DIAPH3-deficient neural stem cells exhibit abnormalities in karyokinesis and cytokinesis, leading to cell cycle arrest, aneuploidy, and mitotic catastrophe. Here, we investigated the role of DIAPH3 in glioma genesis in mouse models. We selectively deleted the Diaph3 and Trp53 genes in the mouse cerebral cortex and thoroughly analyzed single ( Diaph3 cKO and Trp53 cKO) and double (dcKO) conditional knockout mice. The tumors appeared earlier in dcKO than in Trp53 cKO mice, and this was associated with increased whole chromosome copy number alterations, endogenous DNA damage, and shorter survival of dcKO mice. We performed a comparative transcriptomic analysis prior to the onset of tumors and identified changes in cancer gene signatures specifically in dcKO, suggesting that the loss of DIAPH3 hastens the tumorigenic process. We isolated cancer stem-like cells and assessed their sensitivity to ionizing radiation and found that DIAPH3 regulates the resistance of glioma stem-like cells to irradiation. Our data suggest that DIAPH3 has a tumor-suppressor function and that its deficiency promotes aneuploidy and genome instability, accelerating tumorigenesis and leading to early onset of high-grade diffuse glioma with DNA damage, and resistance to ionizing radiation.