E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness.
Frank H C ChengHon-Yi LinTzy-Wei HwangYin-Chen ChenRui-Lan HuangChia-Bin ChangWeiqin YangRu-Inn LinChing-Wen LinGary C W ChenShu-Yuan MaiJora M J LinYu-Ming ChuangJian-Liang ChouLi-Wei KuoChin LiAlfred S L ChengHung-Cheng LaiShu-Fen WuJe-Chiang TsaiMichael Wing-Yan ChanPublished in: Cancer science (2019)
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.
Keyphrases
- long non coding rna
- long noncoding rna
- cell proliferation
- poor prognosis
- transcription factor
- dna methylation
- stem cells
- gene expression
- epithelial mesenchymal transition
- estrogen receptor
- papillary thyroid
- signaling pathway
- genome wide
- squamous cell carcinoma
- high throughput
- cell therapy
- mesenchymal stem cells
- young adults
- lymph node metastasis
- case control
- genome wide identification