The deltex family
protein DTX3 is believed to possess
E3 ubiquitin ligase activity, as it contains a classic RING finger domain. However, its
biological role and the underlying mechanism in
cancer remain largely elusive. Here, we identified DTX3 as a novel mutant p53-interacting
protein in ovarian
carcinoma. Mechanistically, DTX3 mediated mutant p53 ubiquitination and stabilization by perturbing the MDM2-mutant p53 interaction, consequently leading to activation of diverse mutant p53 target genes. Importantly, a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian
carcinomas. Ectopic DTX3 promoted, while depletion of DTX3 suppressed,
ovarian cancer cell proliferation and invasion. Remarkably, the pro-tumorigenic effect of DTX3 is dependent on mutant p53, because ablation of mutant p53 significantly impaired DTX3-induced gene expression and
ovarian cancer cell growth and propagation. Furthermore, DTX3 elevated the expression of mutant p53 target genes and boosted ovarian
tumor growth in vivo. Finally, DTX3 was amplified and overexpressed in ovarian
carcinomas, which is significantly associated with unfavorable prognosis. Altogether, our findings unveil the oncogenic role of DTX3 in
ovarian cancer development by bolstering mutant p53 activity.