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Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development
Genes & Diseases ( IF 6.9 ) Pub Date : 2020-11-21 , DOI: 10.1016/j.gendis.2020.11.007
Shanshan Wang 1, 2 , Qian Hao 1, 2 , Jiajia Li 2, 3 , Yajie Chen 2, 4 , Hua Lu 5 , Xiaohua Wu 2, 3 , Xiang Zhou 1, 2, 6, 7
Affiliation  

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.



中文翻译:

泛素连接酶 DTX3 赋予突变 p53 以促进卵巢癌发展

deltex 家族蛋白 DTX3 被认为具有 E3 泛素连接酶活性,因为它包含一个经典的 RING 指结构域。然而,它在癌症中的生物学作用和潜在机制在很大程度上仍然难以捉摸。在这里,我们将 DTX3 鉴定为卵巢癌中一种新的突变 p53 相互作用蛋白。从机制上讲,DTX3 通过扰乱 MDM2-突变体 p53 相互作用介导突变体 p53 泛素化和稳定化,从而导致多种突变体 p53 靶基因的激活。重要的是,在卵巢癌中进一步验证了 DTX3 和突变 p53 靶基因的表达之间的正相关性。异位 DTX3 促进,而 DTX3 的消耗抑制卵巢癌细胞增殖和侵袭。值得注意的是,DTX3 的促肿瘤作用取决于突变的 p53,因为突变型 p53 的消融显着损害了 DTX3 诱导的基因表达和卵巢癌细胞的生长和增殖。此外,DTX3 提高了突变 p53 靶基因的表达并促进了卵巢肿瘤的生长在体内。最后,DTX3 在卵巢癌中被扩增和过表达,这与不良预后显着相关。总之,我们的研究结果通过增强突变 p53 活性揭示了 DTX3 在卵巢癌发展中的致癌作用。

更新日期:2020-11-21
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