Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance

• Published in: The Journal of biological chemistry Vol. 288; no. 19; pp. 13620 - 13630
• Main Authors: Pan, Wei-Wei, Zhou, Jian-Jie, Liu, Xiao-Man, Xu, Ying, Guo, Lian-Jun, Yu, Chao, Shi, Qing-Hua, Fan, Heng-Yu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.05.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Biology; Cell Line, Tumor; Cell Migration; Cell Movement; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic - metabolism; Chemoresistance; Co-Repressor Proteins; Cystadenoma, Serous - drug therapy; Cystadenoma, Serous - metabolism; Cystadenoma, Serous - secondary; DAXX; DNA Damage; Drug Resistance, Neoplasm; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Expression; Humans; Mice; Mice, Nude; Molecular Chaperones; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian Cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - metabolism; Ovary - pathology; PML; Promyelocytic Leukemia Protein; Radiation Tolerance; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays; Cell Migration; Ovarian Cancer; DAXX; Cell Proliferation; Chemoresistance; DNA Damage; PML
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.446369

Understanding the genes involved in apoptosis and DNA damage responses may improve therapeutic strategies for ovarian cancer. The death domain-associated protein DAXX can be either a pro-apoptotic or an anti-apoptotic factor, depending on the cell type and context. In this study, we found that DAXX was highly expressed in human ovarian surface epithelial tumors but not in granulosa cell tumors. In cultured ovarian cancer cells, DAXX interacted with promyelocytic leukemia protein (PML) and localized to subnuclear domains (so-called PML nuclear bodies). A role for DAXX in ovarian cancer cell proliferation, metastasis, and radio/chemoresistance was examined. Overexpression of DAXX enhanced multiple ovarian cancer cell lines' proliferation, colony formation, and migration, whereas Daxx depletion by RNA interference had the opposite effects. When transplanted into nude mice, ovarian cancer cells that overexpressed DAXX displayed enhanced tumorigenesis capability in vivo, whereas Daxx depletion inhibited tumor development. Importantly, Daxx induced tumorigenic transformation of normal ovarian surface epithelial cells. Daxx also protected ovarian cancer cells against x-irradiation- and chemotherapy-induced DNA damage by interacting with PML. Taken together, our results suggest that DAXX is a novel ovarian cancer oncogene that promotes ovarian cancer cell proliferation and chemoresistance in ovarian cancer cells. Thus, modulating DAXX-PML nuclear body activity may be an effective strategy for preventing the recurrence and chemoresistance of ovarian cancers. Background: The role of DAXX in ovarian cancer development and metastasis has not been investigated before now. Results: Overexpression of DAXX enhanced ovarian cancer cell proliferation, colony formation, and migration, whereas Daxx depletion had the opposite effects. Conclusion: DAXX promotes ovarian cancer cell proliferation and chemoresistance. Significance: Modulating DAXX may be an effective strategy for preventing the recurrence and chemoresistance of ovarian cancers.