TET1-mediated epigenetic reprogramming switches metabolism and promotes malignant phenotypes of ovarian cancer

[[abstract]]Epigenetic dysregulation is one of the mechanisms involved in ovarian cancer carcinogenesis. Recently identified a new epigenetic modulator ten-eleven translocation protein 1 (TET1), a DNA dioxygenase which is believed in DNA demethylation through a 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) conversion, plays an important role in regulating self-renewal and specification in embryonic stem cells. In addition, it works as a tumor suppressor gene by inhibition of cell invasion, migration and tumor growth in breast and prostate cancer. However, the role of TET1 in ovarian cancer remains unknown. Thus we examed the expression level of TET1 in ovarian cancer tissues. We found that TET1 expression level correlated with cancer staging (p = 0.03) in 88 ovarian cancer from our biobank and poor survival (p = 0.012) in TCGA database. High expression of TET1 was observed in advanced stage, high-grade primary tumor specimens in comparison with normal ovarian surface epithelium (OSE) brushings (p = 0.0005) by NCBI database (GSE18520). These results suggested that TET1 may play some roles in ovarian cancer development, which is different from those previously published in other cancers. To study the function of TET1 in ovarian cancer, we generated TET1 over-expressing and knockdown cell lines model, the expression level and enzymatic activities of TET1 were confirmed by real time PCR, western and 5hmC stain. Here we found that TET1 increases the abilities of cell migration, anchorage-independent growth and promotes tumor growth. In addition, TET1 actives cancer stem markers and enhances the abilities of spheroid formation. Ovarian cancer stem cells (OCSCs) from cell line express high level of TET1 while the differentiated progenies suppress TET1 expression. Moreover, seven of eight patient-derived OCSCs revealed high expressing of TET1 in comparison with its parental cancer cells by quantitative PCR. To further examine the TET1 regulation network, we combined the expression array and MethCap-seq to analyze the epigomic changes. We found that a cluster of target genes which were up-regulated through DNA demethylation were enzymes responsible for oxidative phosphorylation. We investigated metabolic status by Extracellular Flux Analyzer (seahourse) on the TET1-overexpressing cells. Compared with control cells, TET1-overexpressing cells revealed 1.7 fold (p = 0.011) increase of oxygen consumption rate (OCR); while the extracellular acidification rate (ECAR) showed no difference (p = 0.856). This bioenergetic metabolism shift may be due to demethylation of subunits of mitochondria complexs. Taken together, TET1 reprograms the epigenome, shifts the metabolism, increases the malignant phenotypes and confers a poor prognosis of ovarian cancer. Targeting mitochondria on TET1-expressing ovarian cancer patients may provide a new way of personalized therapy