Ten-eleven Translocation 1 Expression Research Articles

TET1 is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Papillary Thyroid Cancer.

To investigate the function of ten-eleven translocation 1 (TET1) and its underlying mechanism in papillary thyroid cancer (PTC). Using the RNA-Seq data based on GDC TCGA, we analyzed the gene expression pattern of TET1 in PTC. Immunohistochemistry was carried out to assess the TET1 protein level. Then, its diagnostic and prognostic functions were determined by various bioinformatics approaches. Enrichment analysis was performed to explore the potential pathways in which TET1 is mainly involved. Finally, the immune cell infiltration analysis was conducted and the association of TET1 mRNA expression with the expression levels of immune checkpoints, tumor mutation burden (TMB) score, microsatellite instability (MSI) score, and cancer stem cells (CSC) score was examined. TET1 expression was lower in PTC tissues compared with that in normal tissues (P < 0.01). Besides, TET1 had a certain value in diagnosing PTC, and low-TET1 mRNA expression led to favorable disease-specific survival (DSS) (P < 0.01). The enrichment analysis revealed autoimmune thyroid disease and cytokine-cytokine receptor interaction were the consistent pathways in which TET1 participated. TET1 was negatively correlated with the Stromal score and Immune score. The different proportions of immune cell subtypes were observed between high- and low-TET1 expression groups. Interestingly, TET1 mRNA expression was inversely related to the expression levels of immune checkpoints, and TMB, MSI, and CSC scores. TET1 might be a robust diagnostic and prognostic biomarker for PTC. TET1 affected the DSS of PTC patients possibly through the regulation of immune-related pathways and tumor immunity.

Specific inhibition of TET1 in the spinal dorsal horn alleviates inflammatory pain in mice by regulating synaptic plasticity

DNA demethylation mediated by ten-eleven translocation 1 (TET1) is a critical epigenetic mechanism in which gene expression is regulated via catalysis of 5-methylcytosine to 5-hydroxymethylcytosine. Previously, we demonstrated that TET1 is associated with the genesis of chronic inflammatory pain. However, how TET1 participates in enhanced nociceptive responses in chronic pain remains poorly understood. Here, we report that conditional knockout of Tet1 in dorsal horn neurons via intrathecal injection of rAAV-hSyn-Cre in Tet1fl/fl mice not only reversed the inflammation-induced upregulation of synapse-associated proteins (post-synaptic density protein 95 (PSD95) and synaptophysin (SYP)) in the dorsal horn but also ameliorated abnormalities in dendritic spine morphology and alleviated pain hypersensitivities. Pharmacological blockade of TET1 by intrathecal injection of a TET1-specific inhibitor—Bobcat 339—produced similar results, as did knockdown of Tet1 by intrathecal injection of siRNA. Thus, our data strongly suggest that increased TET1 expression during inflammatory pain upregulates the expression of multiple synapse-associated proteins and dysregulates synaptic morphology in dorsal horn neurons, suggesting that Tet1 may be a potential target for analgesic strategies.

Hypoxia switches TET1 from being tumor-suppressive to oncogenic

The classical oxidizing enzymatic activity of Ten Eleven Translocation 1 (TET1) and its tumor suppressor role are well known. Here, we find that high TET1 expression is associated with poor patient survival in solid cancers often having hypoxia, which is inconsistent with its tumor suppressor role. Through a series of in vitro and in vivo studies, using thyroid cancer as a model, we demonstrate that TET1 plays a tumor suppressor function in normoxia and, surprisingly, an oncogenic function in hypoxia. Mechanistically, TET1 mediates HIF1α-p300 interaction by acting as a co-activator of HIF1α to promote CK2B transcription under hypoxia, which is independent of its enzymatic activity; CK2 activates the AKT/GSK3β signaling pathway to promote oncogenesis. Activated AKT/GSK3β signaling in turn maintains HIF1α at elevated levels by preventing its K48-linked ubiquitination and degradation, creating a feedback loop to enhance the oncogenicity of TET1 in hypoxia. Thus, this study uncovers a novel oncogenic mechanism in which TET1 promotes oncogenesis and cancer progression through a non-enzymatic interaction between TET1 and HIF1α in hypoxia, providing novel therapeutic targeting implications for cancer.

MiR-183-5p promotes renal cell carcinoma metastasis by targeting TET1.

Ten-eleven translocation 1 (TET1) is a member of the DNA demethylase family that regulates the methylation level of the genome. Dysregulation of TET1 in renal cell carcinoma (RCC) may be associated with RCC progression, but the mechanism of TET1 down-regulation in RCC is not yet known. MiR-183-5p is up-regulated in various tumor tissues and acts as an oncogene. We used Transwell and wound healing assays to test cell invasion and migration. To investigate DNA methylation, we used dot blot, which indicates TET1 enzyme activity. We verified the binding of miR-183-5p and TET1 3'-UTR (untranslated region) using dual-luciferase reporter assay. Our study demonstrated, for the first time, that miR-183-5p can directly repress TET1 expression in RCC. We observed a significant decrease in TET1 expression in RCC specimens, as reported in the literature, and a significant decrease in the concentration of 5hmC in RCC. By aligning the microRNA with a database and using the luciferase reporter gene method, we found that miR-183-5p can inhibit luciferase activity by binding to 453-459 bp of TET1 3'-UTR, leading to inhibition of TET1 expression. Furthermore, down-regulation of TET1 inhibited miR-200c expression and promoted RCC cell invasion and migration. Our findings suggest that in RCC, increased expression of miR-183-5p inhibits the expression of TET1, which in turn inhibits the expression of miR-200c and E-cadherin, both of which are associated with cell adhesion. This leads to the promotion of cell invasion and migration.

TET1 mediated male reproductive toxicity induced by Bisphenol A through Catsper-Ca2+ signaling pathway

Bisphenol A (BPA) exposure has many adverse effects on the reproductive system in animals and humans. Ten-eleven translocation 1 (TET1) is closely related to a variety of biological processes through regulating the dynamic balance of DNA demethylation and methylation. However, the role and mechanism of TET1 during BPA induced reproductive toxicity are largely unknown. In this study, mouse spermatogonia cell line GC-2 was treated with BPA in the final concentration of 0, 20, 40 and 80 μM for 72 h. The cell model of differential TET1 gene expression was established to explore the role and mechanism. We found that the growth rate of GC-2 cells, and the intracellular calcium level decreased significantly with the increase of BPA dose, while TET1 and Catsper1-4 expression level decrease with a dose-dependent relationship. Furthermore, TET1 overexpression promoted the proliferation of GC-2 cell, the increase of calcium ion concentration, and the expression level of Catsper1-4, while knockdown of TET1 leads to the opposite results. Mechanistically, TET1 expression promoted the hydroxymethylation of Catsper1-4 and reduced their methylation level. In addition, the expression level of Catsper1-4 was positively correlated with TET1 gene expression level in semen samples of the population. Our study revealed for the first time that TET1 gene regulates the expression of related molecules in the Catsper calcium signal pathway through its hydroxymethylation modification to affect the calcium level, thereby participating in the process of BPA induced damage. These results indicated that TET1 gene may be a potential biomarker of BPA induced male reproductive toxicity.

Loss of ten-eleven translocation 1 (TET1) expression as a diagnostic and prognostic biomarker of endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynecological cancer. However, there is currently no routinely used biomarker for differential diagnosis of malignant and premalignant endometrial lesions. Ten-eleven translocation (TET) proteins, especially TET1, were found to play a significant role in DNA demethylation, via conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1, 5-mC, and 5-hmC expression profiles in endometrial carcinogenesis are currently unclear. We conducted a hospital-based retrospective review of the immunohistochemical expression of TET1, 5-mC, and 5-hmC in 181 endometrial samples. A “high” TET1 and 5-hmC expression score was observed in all cases of normal endometrium (100.0% and 100.0%, respectively) and in most samples of endometrial hyperplasia without atypia (90.9% and 78.8%, respectively) and atypical hyperplasia (90.6% and 93.8%, respectively), but a “high” score was found in only less than half of the EC samples (48.8% and 46.5%, respectively). The TET1 and 5-hmC expression scores were significantly higher in normal endometrium and premalignant endometrial lesions than in ECs (p < 0.001). A “high” 5-mC expression score was observed more frequently for ECs (81.4%) than for normal endometrium (40.0%), endometrial hyperplasia without atypia (51.5%), and atypical hyperplasia (53.1%) (p < 0.001). We also found that TET1 mRNA expression was lower in ECs compared to normal tissues (p = 0.0037). TET1 immunohistochemistry (IHC) scores were highly proportional to the TET1 mRNA levels and we summarize that the TET1 IHC scoring can be used for biomarker determinations. Most importantly, a higher TET1 score in EC cases was associated with a good overall survival (OS) rate, with a hazard ratio (HR) of 0.31 for death (95% confidence interval: 0.11–0.84). Our findings suggest that TET1, 5-mC, and 5-hmC expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. TET1 is also a potential prognostic marker for EC.

Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.

The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten-eleven translocation 1 (TET1) expression, which subsequently increases calcium-activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω-Nitro-L-arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin-eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription-quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.

Ten-Eleven Translocation 1 Promotes Malignant Progression of Cholangiocarcinoma With Wild-Type Isocitrate Dehydrogenase 1.

Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole-genome sequencing data indicate that about 20% of patients with CCA have isocitrate dehydrogenase 1 (IDH1) mutations, which have been suggested to target 2-oxoglutarate (OG)-dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that patients with CCA and mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. This study aimed to clarify if ten-eleven translocation 1 (TET1), which is one of the 2-OG-dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing The Cancer Genome Atlas (TCGA) data set, TET1 mRNA was found to be substantially up-regulated in patients with CCA when compared with noncancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG), which are cosubstrates for TET1 dioxygenase. The treatments with α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity, and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model by targeting cell growth and apoptosis. Our data suggest that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate TET1 expression in CCA tumors before application of the IDH1 mutation inhibitor because the inhibitor suppresses 2-hydroxyglutarate expression, which may result in activation of TET, potentially leading to CCA malignancy.

BACH1 is transcriptionally inhibited by TET1 in hepatocellular carcinoma in a microRNA-34a-dependent manner to regulate autophagy and inflammation

Hepatocellular carcinoma (HCC), one of the main contributors to cancer-associated deaths globally, is characterized by high invasiveness. Herein, we studied the molecular mechanisms underlying ten-eleven translocation 1 (TET1)-mediated autophagy in HCC. Following data mining using GSE101728, GSE14520 and GSE138178, TET1 was screened out, and the differential expression of TET1 was verified by bioinformatics analysis. TET1, one of the prognostic markers in HCC, was poorly expressed in HCC. Through functional experiments, we determined that upregulation of TET1 inhibited the proliferation, migration, invasion, tumorigenesis, metastasis and inflammatory factors of HCC cells, and promoted cell autophagy and apoptosis. Mechanistically, TET1 activated miR-34a by demethylating miR-34a. BTB domain and CNC homology 1 (BACH1) was identified as the target gene of miR-34a. Notably, Downregulation of miR-34a increased cellular inflammatory factors and decreased autophagy in the presence of TET1, while declines in BACH1 suppressed cellular inflammatory factors and enhanced autophagy in the presence of miR-34a inhibitor. BACH1 negatively regulated the p53 pathway. In conclusion, TET1 is a tumor suppressor in the progression of HCC by regulating the miR-34a/BACH1/p53 axis, and may contribute to the improvement of HCC prognosis and therapy.

The Gamma-glutamyltransferase gene of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt signal pathway through up-regulating TET1

AimsHelicobacter pylori (Hp) infection plays an important role in the development of gastric cancer. Hp can secrete gamma-glutamyltransferase (GGT), however, the impact of GGT of Hp on the human gastric cells is not clear. Although it has been demonstrated that ten-eleven translocation 1 (TET1) is overexpressed in gastric cancer, the relationship between the GGT of Hp and TET1 has not been studied. The aim of this study was to explore the relationship between GGT and TET1, and the role of TET1 in the development of gastric cancer induced by Hp was also explored. Materials and methodsThe correlation between TET1 and prognosis of gastric adenoma cancer was analyzed by bioinformatics. The GGT gene of Hp26695 was knocked out by electroporation with plasmid to construct the GGT knockout strain of Hp (Hp-KS-1). The shTET1 lentivirus transfected GES-1, MGC-803 and SGC-7901 cell lines were constructed. The biological characteristics of the three kind of cells were detected. Key findingsTET1 was overexpressed in gastric tissues of Hp infected patients and mice. Bioinformatics analysis showed that in patients with gastric cancer, higher TET1 expression would result in poorer prognosis. The GGT gene of Hp can lead to overexpression of TET1 in GES-1, MGC-803 and SGC-7901 cells, along with the activation of Wnt/β-catenin signaling pathway, and then promoting tumorigenesis. After silencing TET1, the Wnt/β-catenin signaling pathway which was activated by GGT of Hp was inhibited. SignificanceGGT of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt/β-catenin signaling pathway trough up-regulating TET1.

Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis.

The methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is an important regulator for the balance of DNA methylation and hydroxymethylation through various pathways. Increasing evidence has suggested that TET1 probably involved in DNA methylation and demethylation dysregulation during chemical carcinogenesis. However, the role and mechanism of TET1 during lung cancer remains unclear. In this study, we found that TET1 expression was significantly down-regulated and the methylation level was significantly up-regulated in 3-methylcholanthrene (3-MCA) induced cell malignant transformation model, rat chemical carcinogenesis model, and human lung cancer tissues. Demethylation experiment further confirmed that DNA methylation negatively regulated TET1 gene expression. TET1 overexpression inhibited cell proliferation, migration and invasion invitro and invivo, while knockdown of TET1 resulted in an opposite phenotype. DNA hydroxymethylation level in the promoter region of base excision repair (BER) pathway key genes XRCC1, OGG1, APEX1 significantly decreased and the degree of methylation gradually increased in malignant transformed cells. After differential expression of TET1, the level of hydroxymethylation, methylation and expression of these genes also changed significantly. Furthermore, TET1 binds to XRCC1, OGG1, and APEX1 to maintain them hydroxymethylated. Blockade of BER pathway key gene alone or in combination significantly diminished the effect of TET1. Our study demonstrated for the first time that TET1 expression is regulated by DNA methylation and TET1-mediated hydroxymethylation regulates BER pathway to inhibit the proliferation, migration and invasion during 3-MCA-induced lung carcinogenesis. These results suggested that TET1 gene can be a potential biomarker and therapy target for lung cancer.

TET1 may contribute to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis.

BackgroundEndometriosis (EMs) is a non-malignant gynecological disease, whose pathogenesis remains to be clarified. Recent studies have found that hypoxia induces epithelial-mesenchymal transition (EMT) as well as epigenetic modification in EMs. However, the relationship between EMT and demethylation modification under hypoxia status in EMs remains unknown.MethodsThe expression of N-cadherin, E-cadherin and TET1 in normal endometria, eutopic endometria and ovarian endometriomas was assessed by immunohistochemistry and immunofluorescence double staining. 5-hmC was detected by fluorescence-based ELISA kit using a specific 5-hmC antibody. Overexpression and inhibition of TET1 or hypoxia-inducible factor 2α (HIF-2α) were performed by plasmid and siRNA transfection. The expression of HIF-2α, TET1 and EMT markers in Ishikawa (ISK) cells (widely used as endometrial epithelial cells) was evaluated by western blotting. The interaction of HIF-2α and TET1 was analyzed by chromatin immunoprecipitation.ResultsDemethylation enzyme TET1 (ten-eleven translocation1) was elevated in glandular epithelium of ovarian endometrioma, along with the activation of EMT (increased expression of N-cadherin, and decreased expression of E-cadherin) and global increase of epigenetic modification marker 5-hmC(5-hydroxymethylcytosine). Besides, endometriosis lesions had more TET1 and N-cadherin co-localized cells. Further study showed that ISK cells exhibited enhanced EMT, and increased expression of TET1 and HIF-2α under hypoxic condition. Hypoxia-induced EMT was partly regulated by TET1 and HIF-2α. HIF-2α inhibition mitigated TET1 expression changes provoked by hypoxia.ConclusionsHypoxia induces the expression of TET1 regulated by HIF-2α, thus may promote EMT in endometriosis.

(+)4-Cholesten-3-one promotes differentiation of neural stem cells into dopaminergic neurons through TET1 and FoxA2

In this paper, we report the results of treating cells with an effective small molecule, (+)4-cholesten-3-one (PubChem CID: 91477), which can promote neural stem cell(NSC) differentiation into dopaminergic neurons. This study used rat neural stem cells stimulated with two different concentrations (7.8 μM and 78 μM) of (+)4-cholesten-3-one. Cell phenotypic analysis showed that (+)4-cholesten-3-one induced NSC differentiation into dopaminergic neurons, and the level of tyrosine hydroxylase(TH), which is specific for dopaminergic cells, was significantly increased compared with that of the drug-free control group. Furthermore, in this study, we found that this effect may be related to the transcription factor fork-head box a2 (FoxA2) and ten-eleven translocation 1 (TET1). The expression of TET1 and FoxA2 was upregulated after treatment with (+)4-cholesten-3-one. To verify the relationship between (+)4-cholesten-3-one and these genes, we found that the binding rate of TET1 and FoxA2 increased after the application of (+)4-cholesten-3-one, as confirmed by a coimmunoprecipitation (Co-IP) assay. With a small interfering RNA (siRNA) experiment, we found that only when Tet1 and Foxa2 were not silenced was the mRNA level of Th increased after (+)4-cholesten-3-one treatment. Taken together, these data show that (+)4-cholesten-3-one can promote the differentiation of NSCs into dopaminergic neurons by upregulating the expression of TET1 and FoxA2 and by increasing their binding. Thus, (+)4-cholesten-3-one may help address the application of neural stem cell replacement therapy in neurodegenerative diseases.

Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1.

Ten-eleven translocation 1 (TET1) is a member of methylcytosine dioxygenase, which catalyzes 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) to promote the demethylation process. The dysregulated TET1 protein and 5 hmC level were reported to either suppress or promote carcinogenesis in a cancer type-dependent manner. Currently, the role of TET1 in the development of urinary bladder cancer (UBC) and its underlying molecular mechanisms remain unclear. Herein, we found that TET1 expression was downregulated in UBC specimens compared with normal urothelium and was inversely related to tumor stage and grade and overall survival, suggesting its negative association with UBC progression. TET1 silencing in UBC cells increased cell proliferation and invasiveness while the ectopic expression of wild-type TET1-CD, but not its enzymatic inactive mutant, reversed these effects and suppressed tumorigenicity in vivo. In addition, as a direct regulator of TET1 activity, vitamin C treatment increased 5 hmC level and inhibited the anchorage-independent growth and tumorigenicity of UBC cells. Furthermore, we found that TET1 maintained the hypomethylation in the promoter of the AJAP1 gene, which codes for adherens junction-associated protein 1. The downregulation of AJAP1 reversed TET1-CD-induced nuclear translocation of β-catenin, thus inhibiting the expression of its downstream genes. In human UBC specimens, AJAP1 is frequently downregulated and positively associated with TET1. Notably, low expression levels of both TET1 and AJAP1 predict poor prognosis in UBC patients. In conclusion, we found that the frequently downregulated TET1 level reduces the hydroxymethylation of AJAP1 promoter and subsequently activates β-catenin signaling to promote UBC development. The downregulation of both TET1 and AJAP1 might be a promising prognostic biomarker for UBC patients.

MicroRNA-191 regulates endometrial cancer cell growth via TET1-mediated epigenetic modulation of APC

Endometrial cancer (EC) is a common gynecological malignancy with relatively favourable prognosis, although alternative diagnostic and therapeutic options remain to be explored for advanced disease. Recent studies enabled to apply microRNAs (miRs) to clinical cancer management as promising diagnostic and therapeutic biomarkers. We here aimed to identify proliferation-associated miRNAs and characterize their functions in EC cells. Our small RNA-sequencing analysis showed that miR-191 is abundantly expressed in HEC-1A and Ishikawa EC cells along with the high expression of miR-182, which was previously characterized as an EC proliferation-related miRNA in EC. We showed that miR-191 was upregulated in EC tissues than in adjacent normal tissues and its knockdown repressed EC cell proliferation. In silico miRNA target screening identified that ten-eleven translocation 1 (TET1) is one of the putative miR-191 targets. TET1 expression could be downregulated by miR-191 through the mRNA-miRNA interaction in the 3'-untranslated region of TET1. In line with TET1 functions as a methylcytosine dioxygenase, which removes genome-wide DNA methylation marks, decreased TET1 expression resulted in hypermethylation in the promotor region of tumour suppressor adenomatous polyposis coli. Taken together, miR-191 could function as an oncogenic miRNA in EC and serve as a prospective diagnostic and therapeutic target for advanced disease.

Genome-Epigenome-Senescence: Is TET1 a Caretaker of p53-Injured Lung Cancer Cells?

The study by Filipczak and colleagues identified the interplay between mutant p53 proteins and methylcytosine dioxygenase ten-eleven translocation 1 (TET1) in lung cancers. p53 transversion mutations were closely associated with high TET1 expression, which prevented genomic instability-associated cellular senescence. Depletion of TET1 was synergistic with classical antitumor drugs, such as cisplatin or doxorubicin, providing an attractive rationale for targeted therapies against TET1 combined with antitumor drugs in patients with p53-mutant lung cancer.See related article by Filipczak et al., p. 1758.

Metformin sensitizes endometrial cancer cells to progestin by targeting TET1 to downregulate glyoxalase I expression

Progestins has been used widely for endometrial cancer (EC) patients. However, long term use of high dose progestin often lead to progestin resistance. Our previous studies have demonstrated that metformin reversed progestin resistance through the downregulation of the expression of glyoxalase I (GLOI) in type I endometrial cancer. Recent studies have demonstrated the role of Ten-eleven translocation 1 (TET1) in endometrial cancer, but the physiological role of TET1 in GLOI-mediated progestin resistance has been poorly addressed. Immunohistochemistry was used to detect the expression of TET1, GLOI and 5hmC in various endometrium. Western blot was carried out to analyses TET1 and GLOI expression with different treatment. Cell counting kit-8 was used to evaluate cell proliferation after various treatment. Dot blot assay and HMeDIP assay were performed to detect global hydroxmethylation levels and hydroxymethylation levels in GLOI gene respectively. In current study, we found that metformin effectively sensitized progestin in endometrial cancer cell lines through the down regulation of the expression of TET1 and GLOI. Interestingly, the exogenous increase of TET1 expression enhanced total 5hmC level and hydroxymethylation modification in glyoxalase I promoter region. This effect was abated by metformin treatment. Moreover, the expression profile of TET1 and glyoxalase I in various endometrial tissue parallelized with 5hmC level. Therefore, this finding suggests that metformin sensitized progestin in endometrial cancer through the TET1-5hmC-GLOI signaling pathway.

Enhanced expression of ten-eleven translocation 1 reverses gemcitabine resistance in cholangiocarcinoma accompanied by a reduction in P-glycoprotein expression.

Increasing evidence revealed that ten‐eleven translocation 1 (TET1) plays an important role in tumorigenesis and chemoresistance, but its functions in gemcitabine resistance in cholangiocarcinoma (CCA) remain unknown. This study aims to investigate the effect of TET1 on gemcitabine resistance in CCA and the possible effect on P‐glycoprotein (P‐gp) expression encoded by multidrug resistance (MDR) genes. We established two kinds of gemcitabine‐resistant CCA cell lines and confirmed its specific features. The expression of TET1 and P‐gp was evaluated in gemcitabine‐resistant CCA cells and their parental cells at mRNA and protein level by quantitative RT‐PCR and western blot analysis. After transfecting the gemcitabine‐resistant CCA cell lines with TET1 gene or siRNA, the cell viability test was obtained to verify the effect of TET1 on the sensitivity of CCA cells to gemcitabine. And then, the possible effect of TET1 on the expression of P‐gp was examined by western blot analysis. Xenograft tumor experiment was conducted to confirm the association between TET1 and P‐gp expression under gemcitabine chemoresistance. The associations between clinical outcomes of CCA patients with chemotherapy and TET1 expression were analyzed in 82 patients. The results showed that TET1 expression was significantly decreased, and P‐gp expression was increased in gemcitabine‐resistant CCA cells. Additionally, overexpression of TET1 augmented the sensitivity of CCA cells to gemcitabine and induced the decreased expression of P‐gp in gemcitabine‐resistant CCA cells. Furthermore, multivariate Cox regression analysis indicated that TET1 expression and TNM stage were independent risk factors (P < 0.001) for the clinical outcomes of CCA patients with chemotherapy. Additionally, Kaplan‐Meier survival and the log‐rank test showed that decreased expression of TET1 was associated with poorer prognosis of CCA patients with chemotherapy. These findings suggest that TET1 expression reverses gemcitabine resistance in CCA accompanied by a reduction in P‐gp expression. Thus, TET1 may be a promising target to overcome chemoresistance in CCA.

Tet methylcytosine dioxygenase 1 promotes hypoxic gene induction and cell migration in colon cancer.

Ten-eleven translocation 1 (TET1), a widely reported DNA demethylation protein, has been associated with tumorigenesis and metastasis. However, whether TET1 is an oncogene or tumor suppressor gene has been controversial; the mechanism of how TET1 affects cancer progression remains unclear. The current study aims to investigate how TET1 is changed in the tumor microenvironment and to explore the mechanisms of how TET1 affects colon cancer progression. Because hypoxia prevails on solid tumors, we established an important connection between hypoxia and DNA demethylation in tumorigenesis. By qPCR and RNA interference (RNAi) technology, we found that hypoxia increased TET1 expression with a hypoxia-inducible factor-1-alpha (HIF-1α)-dependent manner. By CHIP-qPCR and pyrosequencing technology, we demonstrated that TET1 regulated the target gene expression of HIF-1α through HIF-1α binding to hypoxia-responsive elements (HREs), and HIF-1α binding to HREs depended on CpG methylation levels. By Cell Counting Kit-8 (CCK-8) and transwell assay, we showed that loss of TET1 did not affect cell proliferation but inhibited migration. We also identified two novel gene mutants of TET1 in 120 paired tumor/normal tissue specimens by DNA sequencing and found that TET1 E2082K mutant blocked the TET1-enhanced cell migration. Our results showed that the downregulation of TET1 rescued the abnormally high levels of gene expression resulting from hypoxia in tumors and reduced the migration activity of tumor cells, suggesting a therapeutic role by interference with TET1 in colon cancer treatment. By demonstrating that hypoxia upregulated TET1 and that TET1 drove HIF-1α-responsive genes, we showed that an epigenetic mechanism and tumor microenvironment-driven models coexisted and mutually affected colon cancer.

MiR-129 is involved in the occurrence of uterine fibroid through inhibiting TET1.

To detect the expressions of micro ribonucleic acid (miR)-129 and its target gene in uterine fibroid tissues and to investigate the role of miR-129 in the occurrence of uterine fibroid. The expressions of miR-129 and its target gene ten-eleven translocation 1 (TET1) were detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Dual-luciferase reporter gene and Western blotting were used to verify the regulatory relation between miR-129 and target gene. The effects of miR-129 on the proliferation, apoptosis, cycle and extracellular matrix (ECM) of uterine fibroid cells were investigated via transfection with miR-129 mimics and TET1 small-interfering RNA (siRNA). MiR-129 was lowly expressed in uterine fibroid. The expression of miR-129 was regulated by sex hormones. The highly expressed miR-129 promoted apoptosis and inhibited proliferation through reducing the low expression of TET1. At the same time, miR-129 affected the accumulation of ECM. The expression of miR-129 in uterine fibroid is lower, and the proliferation capacity of tumor cells is enhanced, thus promoting the occurrence and development of uterine fibroid.