Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development

Shanshan Wang; Qian Hao; Jiajia Li; Yajie Chen; Hua Lu; Xiaohua Wu; Xiang Zhou

doi:10.1016/j.gendis.2020.11.007

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Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development

更新时间：2022-06-24

- Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development
- Genes & Diseases Vol. 9, Issue 3, (2022)
- 作者机构：
  
  1. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University,Shanghai,PR China,200032
  2. Department of Oncology, Shanghai Medical College, Fudan University,Shanghai,PR China,200032
  3. Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Fudan University,Shanghai,PR China,200032
  4. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University,Shanghai,PR China,200032
  5. Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine,LA,New Orleans,USA,70112
  6. Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University,Shanghai,PR China,200032
  7. Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University,Shanghai,PR China,200032
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2020.11.007
  CLC：
- Published：2022，
  
  Published Online：1 May 2022，
扫描看全文
Shanshan Wang, Qian Hao, Jiajia Li, et al. Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development. [J]. Genes & Diseases 9(3).(2022)
DOI：

Shanshan Wang, Qian Hao, Jiajia Li, et al. Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development. [J]. Genes & Diseases 9(3).(2022) DOI： 10.1016/j.gendis.2020.11.007.

摘要

Abstract

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.

关键词

Keywords

DTX3E3 ubiquitin ligaseInvasionMutant p53Ovarian cancerProliferation

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