TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

Chen, Lin Yu; Huang, Rui; Chan, Michael W.Y.; Yan, Pearlly S.; Huang, Tien Shuo; Wu, Ren‐Chin; Rahmanto, Yohan Suryo; Su, Po Hsuan; Weng, Yu Chun; Chou, Jian Liang; Chao, Tai-Kuang; Wang, Yu Chi; Shih, Ie Ming; Lai, Hung Cheng

doi:10.1002/path.5266

Cited by 24 publications

(22 citation statements)

References 64 publications

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“…[ 12 ] Nevertheless, this study was limited by the fact only TET1 deletion was studied, and thus, the effect of low expression and high expression of TET1 is lacking. Furthermore, a study from Chen et al [ 23 ] showed that TET1 expression correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC), as well as cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), which is currently considered as a type II EOC precursor, and inversely correlated with TP53 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), which is currently considered as a type II EOC precursor, and inversely correlated with TP53 mutations. [ 23 ] Further, TET1 could activate multiple oncogenic pathways by demethylating the epigenome, including an immunomodulation network having casein kinase II subunit alpha (CK2±) as a hub. [ 23 ] These differences may be as a result of the differing cell origins.…”

Section: Discussionmentioning

confidence: 99%

“…[ 23 ] Further, TET1 could activate multiple oncogenic pathways by demethylating the epigenome, including an immunomodulation network having casein kinase II subunit alpha (CK2±) as a hub. [ 23 ] These differences may be as a result of the differing cell origins.…”

Section: Discussionmentioning

confidence: 99%

“…Many clinical studies have revealed that the expression of TET1 is closely associated with survival rates in cancer patients with solid tumors, including gastric cancer, [ 15 , 18 , 24 ] cholangiocarcinoma, [ 11 ] hepatocellular cancer, [ 22 ] lung cancer, [ 14 , 21 ] breast cancer, [ 10 , 12 , 17 , 20 ] endometrial cancer, [ 16 ] renal cell cancer, [ 19 ] colorectal cancer, [ 13 ] and ovarian cancer. [ 23 ] Nevertheless, the consistency of the prognostic effect of TET1 remains unclear. So, all published evidence was systematically examined in this meta-analysis to reveal any association between TET1 and the prognosis of patients with different types of solid cancers.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic role of high TET1 expression in patients with solid tumors

Wang

Fan³

et al. 2020

Medicine

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Background: Recently, increased expression of TET1 has been shown to inhibit tumor development in many studies. Therefore, a meta-analysis was conducted to assess the prognostic role of TET1 in solid tumors. Methods: PubMed, Embase, and the Web of Science (last updated on June 13, 2019) were searched and 16 eligible studies involving 3100 patients were eventually taken forward into the meta-analysis. Results: Pooled results indicated that higher TET1 expression in cancer tissues was associated with improved overall survival (OS) [hazard ratio (HR) = 0.736, 95% confidence interval (95% CI) = 0.542–0.998, P = .049]. In the subgroup analysis, higher TET1 expression in respiratory tumors (HR = 0.778, 95% CI = 0.639–0.946, P = .012) and breast cancer in Asian patients (HR = 0.326, 95% CI = 0.199–0.533, P < .001) were significantly associated with better OS. In addition, the association between high TET1 expression and prolonged OS was also statistically significant in the following subgroups; data source from samples (HR = 0.561, 95% CI = 0.384–0.819, P = .003), reported in text (HR = 0.539, 95% CI = 0.312–0.931, P = .027), TET1 protein (HR = 0.635, 95% CI = 0.409–0.984, P = .042), Asians (HR = 0.563, 95% CI = 0.376–0.844, P = .005). Conclusion: This meta-analysis displays that high expression levels of TET1 in tissues is significantly associated with better survival in patients with solid tumors. This finding can be used as evidence to the tone that TET1 may be a useful target for the treatment of patients with solid tumors in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic role of high TET1 expression in patients with solid tumors

Wang

Fan³

et al. 2020

Medicine

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“…OC patients with high expression of Cyclin-dependent kinase 9 (CDK9) in relapsed and metastatic lesions have a worse prognosis than patients with low expression of CDK9 [9]. A number of studies in transcription and epigenetics have confirmed that the occurrence, development, and therapeutic efficacy of OC are influenced by the dynamic changes of multiple oncogenes and tumor suppressor genes [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

A nine-gene signature related to tumor microenvironment predicts overall survival with ovarian cancer

Ding

Dong

Wang

et al. 2020

Aging

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Mounting evidence suggests that immune cell infiltration within the tumor microenvironment (TME) is a crucial regulator of carcinogenesis and therapeutic efficacy in ovarian cancer (OC). In this study, 593 OC patients from TCGA were divided into high and low score groups based on their immune/stromal scores resulting from analysis utilizing the ESTIMATE algorithm. Differential expression analysis revealed 294 intersecting genes that influencing both the immune and stromal scores. Further Cox regression analysis identified 34 differentially expressed genes (DEGs) as prognostic-related genes. Finally, the nine-gene signature was derived from the prognostic-related genes using a Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression. This nine-gene signature could effectively distinguish the high-risk patients in the training (TCGA database) and validation (GSE17260) cohorts (all p < 0.01). A time-dependent receiver operating characteristic (ROC) analysis showed that the nine-gene signature had a reasonable predictive accuracy (AUC = 0.707, AUC =0.696) in both cohorts. In addition, this nine-gene signature is associated with immune infiltration in TME by Gene Set Variation Analysis (GSVA), and can be used to predict the survival of patients with OC.

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Downregulation of 5‐hydroxymethylcytosine is an early event in pancreatic tumorigenesis

Fujikura

Alruwaii

Haffner

et al. 2021

The Journal of Pathology

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Epigenetic alterations are increasingly recognized as important contributors to the development and progression of pancreatic ductal adenocarcinoma. 5‐hydroxymethylcytosine (5hmC) is an epigenetic DNA mark generated through the ten‐eleven translocation (TET) enzyme‐mediated pathway and is closely linked to gene activation. However, the timing of alterations in epigenetic regulation in the progression of pancreatic neoplasia is not well understood. In this study, we hypothesized that aberrant expression of ten‐eleven translocation methylcytosine dioxygenase 1 (TET1) and subsequent global 5hmC alteration are linked to early tumorigenesis in the pancreas. Therefore, we evaluated alterations of 5hmC and TET1 levels using immunohistochemistry in pancreatic neoplasms (n = 380) and normal ducts (n = 118). The study cohort included representation of the full spectrum of precancerous lesions from low‐ and high‐grade pancreatic intraepithelial neoplasia (n = 95), intraductal papillary mucinous neoplasms (all subtypes, n = 129), intraductal oncocytic papillary neoplasms (n = 12), and mucinous cystic neoplasms (n = 144). 5hmC and TET1 were significantly downregulated in all types of precancerous lesion and associated invasive pancreatic ductal adenocarcinomas compared with normal ductal epithelium (all p < 0.001), and expression of 5hmC positively correlated with expression of TET1. Importantly, downregulation of both 5hmC and TET1 was observed in most low‐grade precancerous lesions. There were no clear associations between 5hmC levels and clinicopathological factors, thereby suggesting a common epigenetic abnormality across precancerous lesions. We conclude that downregulation of 5hmC and TET1 is an early event in pancreatic tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

Cited by 24 publications

References 64 publications

Prognostic role of high TET1 expression in patients with solid tumors

Prognostic role of high TET1 expression in patients with solid tumors

A nine-gene signature related to tumor microenvironment predicts overall survival with ovarian cancer

Downregulation of 5‐hydroxymethylcytosine is an early event in pancreatic tumorigenesis

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