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

时间:2013年03月10日 访问次数:2083

J Biol Chem. 2013, 288(19):13620-13630.

Wei-Wei Pan, Jian-Jie Zhou, Xiao-Man Liu, Ying Xu, Lian-Jun Guo1, Chao Yu, Qing-Hua Shi, Heng-Yu Fan*

Abstract

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 sub-nuclear domains (so-called PML nuclear bodies). A role for DAXX in ovarian cancer cell proliferation, metastasis, and radio/chemoresistance was examined. Over-expression 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 over-expressed 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.

全文链接:http://www.jbc.org/content/288/19/13620.long