期刊
MOLECULAR CANCER RESEARCH
卷 7, 期 2, 页码 210-220出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-08-0255
关键词
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资金
- University of Alabama Specialized Program of Research Excellence in Ovarian Cancer [P50 CA 083591]
- Gail Parkirs Ovarian Awareness Foundation
- National Cancer Institute [T32 CA 093245]
- Director of Office of Science, Office of Basic Energy Sciences of the U.S. Department of Energy [DE-AC02-05CH11231]
- U.S. Army Medical Research and Materiel Command [BC 061995]
- NIH, National Cancer Institute [P50 CA 58207, P50 CA 83639, P30 CA 82103, U54 CA 112970, U24 CA 126477, P01 CA 64602]
- National Human Genome Research Institute [U24 CA 126551]
- SmithKline Beecham
Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NC160 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NC160 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NC160 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function. (Mol Cancer Res 2009;7(2):210-20)
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