Malignant mesothelioma is highly lethal and the prognosis following therapy is very poor. The effect of radiation monotherapy for mesothelioma is reported to be minimal. To improve the efficacy of radiotherapy, a novel molecular-targeted radiosensitizing agent is needed to increase radiosensitivity of mesothelioma cells. We have previously identified ZDHHC8 as a novel radiation susceptibility gene based on the functional screening in human cells. In this study, we analyzed the effect of ZDHHC8 knockdown with radiation on mesothelioma cells and assessed the therapeutic efficacy in mouse model. In mesothelioma cells, knockdown of ZDHHC8 by siRNA significantly reduced cell survival after irradiation, induced the impairment of G2/M checkpoint, and increased the frequency of cells with micronuclei and apoptosis. In the mouse model, the treatment with ZDHHC8 siRNA and irradiation significantly suppressed tumor growth and increased apoptosis, whereas ZDHHC8 siRNA alone did not. These results suggest that ZDHHC8 knockdown with X-irradiation induced chromosomal instability and cell death including apoptosis through the defects of G2/M checkpoint, and the combination of ZDHHC8 depletion and irradiation has the potential to be effective therapy for malignant mesothelioma.14th International Congress of Radiation Research(ICRR’2011
