Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

Ichimura, Norihisa; Shinjo, Keiko; An, Byonggu; Shimizu, Yasuhiro; Yamao, Kenji; Ohka, Fumiharu; Katsushima, Keisuke; Hatanaka, Akira; Tojo, Masayuki; Yamamoto, Eiko; Suzuki, Hiromu; Ueda, Minoru; Kondo, Yutaka

doi:10.1158/1940-6207.capr-14-0306

Cited by 47 publications

(40 citation statements)

References 33 publications

(50 reference statements)

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“…We found that CRCs in the CIMP-high category showed significantly lower levels of TET1 expression than CIMP-low or CIMP-negative tumors (Fig 1A), which is consistent with previous observations [18]. We next carried out RT-qPCR with TET1 in a series of CRC cell lines, and found that the majority of CRC lines (8 of 12) expressed lower levels of TET1 than normal colonic tissues, whereas two lines (Colo320DM and CaCO2) showed upregulated TET1 expression (Fig 1B).…”

Section: Resultssupporting

confidence: 93%

“…Furthermore, we and others recently reported that TET1 is silenced in association with promoter CpG island hypermethylation in a subset of CRC cell lines [18]. TET1 methylation is preferentially observed in CIMP-positive primary CRCs as well as in CIMP-positive colorectal adenomas [18]. Methylation of TET1 CpG island in primary CRC is also reported by another group recently [19].…”

Section: Introductionsupporting

confidence: 64%

“…We previously showed that the TET1 gene is preferentially methylated in CIMP-positive and BRAF mutant CRCs and adenomas, which suggests TET1 is one of the genes affected by CIMP-related hypermethylation [18]. From those results, however, we could not determine whether TET1 methylation is merely a consequence of CIMP or whether loss of TET1 contributed to aberrant DNA methylation.…”

Section: Discussionmentioning

confidence: 88%

“…Although IDH1/2 mutations have not been reported in CRC, whole exome sequencing analysis identified mutations in all three TET family genes in CRC [17]. Furthermore, we and others recently reported that TET1 is silenced in association with promoter CpG island hypermethylation in a subset of CRC cell lines [18]. TET1 methylation is preferentially observed in CIMP-positive primary CRCs as well as in CIMP-positive colorectal adenomas [18].…”

Section: Introductionmentioning

confidence: 99%

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TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells

et al. 2016

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Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2’-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2’-deoxycytidine in CRC cells.

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Section: Resultssupporting

confidence: 93%

Section: Introductionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells

et al. 2016

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“…Although TETs mutation in CRC is rarely studied, alteration of their methylation is frequently addressed. Norihisa Ichimura et al demonstrated TET1 methylation could contribute to CRC, thus aiding in CRC diagnosis [78]. Another study confirmed TET1 was involved in cancer cells proliferation via WNT signal pathway.…”

Section: Demethylation Via 5hmc Conversion In Cancermentioning

confidence: 99%

Physiological and pathological implications of 5-hydroxymethylcytosine in diseases

et al. 2016

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Gene expression is the prerequisite of proteins. Diverse stimuli result in alteration of gene expression profile by base substitution for quite a long time. However, during the past decades, accumulating studies proved that bases modification is involved in this process. CpG islands (CGIs) are DNA fragments enriched in CpG repeats which mostly locate in promoters. They are frequently modified, methylated in most conditions, thereby suggesting a role of methylation in profiling gene expression. DNA methylation occurs in many conditions, such as cancer, embryogenesis, nervous system diseases etc. Recently, 5-hydroxymethylcytosine (5hmC), the product of 5-methylcytosine (5mC) demethylation, is emerging as a novel demethylation marker in many disorders. Consistently, conversion of 5mC to 5hmC has been proved in many studies. Here, we reviewed recent studies concerning demethylation via 5hmC conversion in several conditions and progress of therapeutics-associated with it in clinic. We aimed to unveil its physiological and pathological significance in diseases and to provide insight into its clinical application potential.

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Comprehensive analysis of 5‐hydroxymethylcytosine in zw10 kinetochore protein as a promising biomarker for screening and diagnosis of early colorectal cancer

Dang

et al. 2020

Clinical & Translational Med

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Background As a new epigenetic biomarker, 5‐hydroxymethylcytosine (5hmC) is broadly involved in various diseases including cancers. However, the function and diagnostic performance of 5hmC in colorectal cancer (CRC) remain unclear. Results High‐throughput sequencing was used to profile 5hmC levels in adjacent normal colon, advanced adenomas, and CRC. The expression and 5hmC levels in zw10 kinetochore protein (ZW10) were significantly increased in the tissues and blood samples for patients with advanced adenoma and CRC, and were much higher in the early stages of CRC (I and II). The receiver operating characteristic analysis had potential diagnostic value for CRC. The area under the curve (AUC) of ZW10 5hmC levels in tissue samples of CRC was 0.901. In blood samples, the AUC was 0.748 for CRC. In addition, the ZW10 5hmC level had much higher diagnostic performance in early stages of CRC (AUC = 0.857) than it did in advanced stages (AUC = 0.594). Compared with FHC cell, ZW10 expression in HT29 cell was significantly increased. The ZW10 knockdown could inhibit cell proliferation and the ZW10 overexpression could promote cell proliferation in HT‐29 cell. Furthermore, ZW10 knockdown inhibited AKT and mTOR phosphorylation, and ZW10 overexpression promoted AKT and mTOR phosphorylation. Conclusions The ZW10 5hmC level may serve as an effective epigenetic biomarker for minimally invasive screening and diagnosis of CRC, and it has higher diagnostic performance in early stages of CRC than it does in advanced stages. In addition, ZW10 could regulate CRC progression through the AKT‐mTOR signaling.

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Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

Cited by 47 publications

References 33 publications

TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells

TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells

Physiological and pathological implications of 5-hydroxymethylcytosine in diseases

Comprehensive analysis of 5‐hydroxymethylcytosine in zw10 kinetochore protein as a promising biomarker for screening and diagnosis of early colorectal cancer

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