Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression

Ibrahim, Ashraf E.K.; Arends, Mark J.; Silva, Ana Luísa; Wyllie, Andrew H.; Greger, Liliana; Itō, Yoko; Vowler, Sarah L.; Huang, Tim H.M.; Tavaré, Simon; Murrell, Adele; Brenton, James D.

doi:10.1136/gut.2010.223602

Cited by 133 publications

(110 citation statements)

References 54 publications

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“…In PPARG-negative cells, UHRF1 is, in fact, recruited on the PPARG promoter where it interacts with other regulatory factors required for DNA and histone methylation. In agreement with the data in the literature, DNMT3b is recruited on the PPARG promoter providing support to its involvement in gene repression and colon tumorigenesis (Linhart et al, 2007;Nosho et al, 2009;Ibrahim et al, 2011). DNMT1 and DNMT3a seem to have a lower impact on PPARG silencing as they are not recruited on the promoter; the differential recruitment of DNMT3a may reflect the very low protein levels detected in the cells analyzed.…”

Section: Discussionsupporting

confidence: 78%

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

et al. 2012

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Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

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Section: Discussionsupporting

confidence: 78%

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

et al. 2012

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“…Furthermore, the efficiency of DNA methylation may be affected by age (12,29). Finally, neoplasia may induce "field-effect" hypomethylation in cancer and surrounding histologically normal tissues, through sequestration of DNA methylation enzymes and substrates by rapidly proliferating, dividing cancer cells, resulting in failure of DNA methylation maintenance in surrounding tissue (11,(30)(31)(32)(33)(34)(35).…”

Section: Causes and Consequences Of Genome-wide Hypomethylationmentioning

confidence: 99%

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

Brennan

Flanagan

2012

Cancer Prevention Research

103

104

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Cancer cells display widespread genetic and epigenetic abnormalities, but the contribution to disease risk, particularly in normal tissue before disease, is not yet established. Genome-wide hypomethylation occurs frequently in tumors and may facilitate chromosome instability, aberrant transcription and transposable elements reactivation. Several epidemiologic case-control studies have reported genomic hypomethylation in peripheral blood of cancer patients, suggesting a systemic effect of hypomethylation on disease predisposition, which may be exploited for biomarker development. However, more recent studies have failed to reproduce this. Here, we report a meta-analysis, indicating a consistent inverse association between genomic 5-methylcytosine levels and cancer risk [95% confidence interval (CI), 1.2-6.1], but no overall risk association for studies using surrogates for genomic methylation, including methylation at the LINE-1 repetitive element (95% CI, 0.8-1.7). However, studies have been highly heterogeneous in terms of experimental design, assay type, and analytical methods. We discuss the limitations of the current approaches, including the low interindividual variability of surrogate assays such as LINE1 and the importance of using prospective studies to investigate DNA methylation in disease risk. Insights into genomic location of hypomethylation, from recent whole genome, highresolution methylome maps, will help address this interesting and clinically important question. Cancer Prev Res; 5(12); 1345-57. Ó2012 AACR.

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“…13 Previous studies have shown a significant increase in DNMT3B enzyme from the normal epithelium to hyperplastic one and from hyperplastic epithelium to carcinoma. 8 This significant finding related to the DNA hypermethylation can be observed in the sub-panel of CIMP, including CAC-NA1G, NEUROG1, CDKN2A, and hMLH1 genes. Increased amount of DNMT3B mRNA in colon cancer tissues, in comparison with normal tissues, is shown in several studies.…”

Section: Introductionmentioning

confidence: 93%

“…The modified pattern of DNA methylation can alter the expression of genes associated with cancer. 8 Decreased global DNA methylation, seen in the malignancy process, alters genomic stability too.…”

Section: Introductionmentioning

confidence: 99%

MiR-339 and especially miR-766 reactivate the expression of tumor suppressor genes in colorectal cancer cell lines through DNA methyltransferase 3B gene inhibition

Afgar

Fard-Esfahani

Mehrtash

et al. 2016

Cancer Biology & Therapy

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It is observed that upregulation of DNMT3B enzyme in some cancers, including colon cancer, could lead to silencing of tumor suppressor genes. MiR-339 and miR-766 have been predicted to target 3 0 UTR of DNMT3B gene. Luciferase reporter assay validated that individual and co-transfection of miR-766 and miR-339 into the HEK293T cell reduced luciferase activity to 26% § 0.41%, 43% § 0.42 and 64% § 0.52%, respectively, compared to the control (P < 0.05). Furthermore, transduction of miR-339 and miR-766 expressing viruses into colon cancer cell lines (SW480 and HCT116) decreased DNMT3B expression (1.5, 3-fold) and (3, 4-fold), respectively. In addition, DNA methylation of some tumor suppressor genes decreased. Expression of these genes such as SFRP1 (2 and 1.6-fold), SFRP2 (0.07 and 4-fold), WIF1 (0.05 and 4-fold), and DKK2 (2 and 4-fold) increased in SW-339 and SW-766 cell lines; besides, expression increments for these genes in HCT-339 and HCT-766 cell lines were (2.8, 4-fold), (0.005, 1.5-fold), (1.7 and 3-fold) and (0.04, 1.7-fold), respectively. Also, while in SW-766, cell proliferation reduced to 2.8% and 21.7% after 24 and 48 hours, respectively, SW-339 showed no reduced proliferation. Meanwhile, HCT-766 and HCT-339 showed (3.5%, 12.8%) and (18.8%, 33.9%) reduced proliferation after 24 and 48 hours, respectively. Finally, targeting DNMT3B by these miRs, decreased methylation of tumor suppressor genes such as SFRP1, SFRP2, WIF1 and DKK2 in the mentioned cell lines, and returned the expression of these tumor suppressor genes which can contribute to lethal effect on colon cancer cells and reducing tumorigenicity of these cells.

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Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression

Abstract: Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.

Cited by 133 publications

References 54 publications

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

MiR-339 and especially miR-766 reactivate the expression of tumor suppressor genes in colorectal cancer cell lines through DNA methyltransferase 3B gene inhibition

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