@article{6cc3b93fb97349faabe1b65dea82410e,
title = "E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness",
abstract = "Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long-term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen-mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c-Kit, by epigenetic silencing the tumor suppressor miR-193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c-KIT, but downregulated miR-193a. Luciferase assays further confirmed that microRNA-193a targets both E2F6 and c-Kit. Interestingly, ChIP-PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR-193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR-193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR-193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen-mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA-193a activity, promoting ovarian cancer stemness and tumorigenesis.",
keywords = "ceRNA, E2F6, epigenetics, miR-193a, ovarian cancer, Up-Regulation/drug effects, MicroRNAs/genetics, Humans, Neoplastic Stem Cells/drug effects, Epigenesis, Genetic/drug effects, Estrogens/adverse effects, E2F6 Transcription Factor/genetics, Female, Ovarian Neoplasms/etiology, Transcription, Genetic/drug effects, Genes, Tumor Suppressor/physiology, Mice, SCID, Epithelial Cells/drug effects, RNA/genetics, Animals, Mice, Nude, DNA Methylation/drug effects, Cell Line, Tumor, Mice, Mice, Inbred BALB C",
author = "Cheng, {Frank H.C.} and Lin, {Hon Yi} and Hwang, {Tzy Wei} and Chen, {Yin Chen} and Huang, {Rui Lan} and Chang, {Chia Bin} and Weiqin Yang and Lin, {Ru Inn} and Lin, {Ching Wen} and Chen, {Gary C.W.} and Mai, {Shu Yuan} and Lin, {Jora M.J.} and Chuang, {Yu Ming} and Chou, {Jian Liang} and Kuo, {Li Wei} and Chin Li and Cheng, {Alfred S.L.} and Lai, {Hung Cheng} and Wu, {Shu Fen} and Tsai, {Je Chiang} and Chan, {Michael W.Y.}",
note = "Funding Information: 2Epigenomics and Human Disease Research Center, National Chung Cheng University, Chia-Yi, Taiwan 3Department of Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan 4School of Medicine, Tzu Chi University, Hualien, Taiwan 5Department of Mathematics, National Chung Cheng University, Chia-Yi, Taiwan 6Department of Obstetrics and Gynecology, School of Medicine, College of Medicine and Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 7School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China 8Department of Mathematics, National Tsing Hua University, Hsin-Chu, Taiwan 9Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Chia-Yi, Taiwan 10Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Funding Information: This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 107-2115-M-007-011-MY2, 106-2 9 2 3 - B - 1 9 4 - 0 0 1 - M Y 3 , 1 0 5 - 2 1 1 5 - M - 1 9 4 - 0 0 9 , 1 0 4 - 2 1 1 5 - M - 1 9 4 - 0 1 1 - M Y 3 , 1 0 4 - 2 1 1 5 - M - 1 9 4 - 0 0 9 , 1 0 4 - 2 3 2 0 - B - 1 9 4 - 0 0 3 , 1 0 3 - 2 3 2 0 - B - 1 9 4 - 002, 102-2320-B-194-006), Buddhist Dalin Tzu Chi Hospital (DTCRD 105(2)-I-10, 106(2)-E-18). This study was also supported by the Center for Innovative Research on Aging Society (CIRAS) and partially supported by MOST, National Center for Theoretical Science (NCTS), and the Brain Research Center (to J.-C. Tsai) from The Featured Areas Research Center Program under the framework of the Higher Education Sprout Project by Ministry of Education, Taiwan. Publisher Copyright: {\textcopyright} 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",
year = "2019",
month = mar,
doi = "10.1111/cas.13920",
language = "English",
volume = "110",
pages = "1085--1095",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "3",
}
