Abstract:Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of and play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-neg… Show more
“…At a functional level, the restoration of TET2 activity in the LN229 glioblastoma cell line reduced cell proliferation in vitro , and tumor growth in vivo , which is in agreement with previous work suggesting that TET2 has antitumor activity in leukemias [ 21 , 54 ] and in other types of tumors including parathyroid carcinoma [ 55 ], colorectal cancer [ 20 ] and glioma [ 53 ]. These results, then, suggest that TET2 activity is frequently disrupted in cancer through different molecular mechanisms and that this process might contribute to malignant transformation.…”
Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma.
“…At a functional level, the restoration of TET2 activity in the LN229 glioblastoma cell line reduced cell proliferation in vitro , and tumor growth in vivo , which is in agreement with previous work suggesting that TET2 has antitumor activity in leukemias [ 21 , 54 ] and in other types of tumors including parathyroid carcinoma [ 55 ], colorectal cancer [ 20 ] and glioma [ 53 ]. These results, then, suggest that TET2 activity is frequently disrupted in cancer through different molecular mechanisms and that this process might contribute to malignant transformation.…”
Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma.
BackgroundSmall intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs.MethodsThe analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines.ResultsVariable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor).ConclusionsSI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4579-z) contains supplementary material, which is available to authorized users.
“…The TET2 protein is a critical regulator of DNA hydroxymethylation. In recent years, TET2-induced DNA hydroxymethylation has been associated with critical regulation of the molecular pathogenesis of various diseases (11,24,25). Immune responses related to Thelper-cell differentiation are regulated by epigenetic changes (26).…”
Section: Discussionmentioning
confidence: 99%
“…2D). Previous studies have indicated that TET2 acts as a key epigenetic regulator (11,12). We next explored the expression levels of TET2 in the lesional skin of mice.…”
Section: Knockdown Of Tet2 Alleviated the Morphological And Histologimentioning
confidence: 99%
“…The newly characterized 5-hmC is commonly differentially expressed in various types of disorders. TET2 is expressed in several differentiated tissues and has been studied in a variety of diseases, such as haematopoietic diseases, immune system disorders and cancer (11)(12)(13)(14). TET2 has been positively associated with 5-hmC and regulation of other elements (15).…”
Epigenetics plays an important role in the development and progression of many diseases. There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis. The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation-2 (TET2) in psoriasiform dermatitis in mice. Immunohistochemical staining was performed on psoriasis patients and healthy controls. Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis. In comparison with healthy controls, 5-hmC was more extensive and intense in the skin lesions from psoriasis patients. TET2 and 5-hmC were highly expressed in imiquimod-induced psoriasiform skin lesions. Importantly, knockdown of TET2 expression in mice attenuated the psoriasiform phenotype and the expression levels of proinflammatory cytokines (interleukin-17A and -17F and interferon-?) and the chemokine CXCL1 in the lesional skin of mice. This is the first demonstration of a critical role for TET2 in psoriasiform dermatitis in a mouse model, and indicates that 5-hmC may serve as a potential biomarker of psoriasis.
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