Yin yang 1 modulates taxane response in epithelial ovarian cancer.
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 NCI60 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 NCI60 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 NCI60 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.
Matsumura
Noriomi
N
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA.
Huang
Zhiqing
Z
Baba
Tsukasa
T
Lee
Paula S
PS
Barnett
Jason C
JC
Mori
Seiichi
S
Chang
Jeffrey T
JT
Kuo
Wen-Lin
WL
Gusberg
Alison H
AH
Whitaker
Regina S
RS
Gray
Joe W
JW
Fujii
Shingo
S
Berchuck
Andrew
A
Murphy
Susan K
SK
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001665:Binding Sites; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D055028:Comparative Genomic Hybridization; D000077143:Docetaxel; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D017239:Paclitaxel / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D043823:Taxoids / Q000627:therapeutic use; D014945:Wound Healing; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*
D000972:Antineoplastic Agents, Phytogenic; D050684:E2F Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043823:Taxoids; D050986:YY1 Transcription Factor; D000077143:Docetaxel; D017239:Paclitaxel; D002945:Cisplatin