Defective binding of transcriptional repressor ZEB via DNA methylation contributes to increased constitutive levels of p73 in Fanconi anemia cells

Pipaón, Carlos; Real, Pedro J.; Fernández-Luna, José L.

doi:10.1016/j.febslet.2005.07.026

Cited by 16 publications

(12 citation statements)

References 16 publications

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“…While it is true that there is a general (but not absolute) inverse correlation between DNA methylation in the promoter region and transcript levels, our finding is not unusual since methylation within the body of genes and distal to genes is often positively correlated with transcript levels (37,38). Specific mechanisms involving binding efficiency of transcriptional repressor(s) to methylated regions for example, may also result in changes in expression (39). This mechanism may be relevant here, since the assessed CpGs are all in the 5 0 region of genes.…”

Section: Discussionmentioning

confidence: 74%

Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients

Leclerc

Lévesque

Cao

et al. 2013

Cancer Prevention Research

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An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr þ/À BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to MthfrBALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon. Cancer Prev Res; 6(11);

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Section: Discussionmentioning

confidence: 74%

Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients

Leclerc

Lévesque

Cao

et al. 2013

Cancer Prevention Research

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“…ZEB1 has been reported tightly associated with cancer initiation, invasion, chemo-resistance, and radio-resistance in various types of cancers [16,17]. A few reports also have indicated the association between ZEB1 and DNA methylation, such as defective binding of ZEB1 results into hypomethylation which contributes to increased constitutive levels of p73 [18]. Additionally, ZEB1 can downregulate E-cadherin expression via recruiting histone deacetylases HDAC1 and HDAC2 in pancreatic cancer [19].…”

Section: Discussionmentioning

confidence: 93%

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells

et al. 2015

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Lung cancer is the most common type of malignant tumor, but the molecular mechanisms for lung cancer progression remains to be elusive. Here, we demonstrated that FBP1 (Fructose-1, 6-bisphosphatase) was frequently down-regulated in lung cancer tissues and cells, and FBP1 down-regulation was associated with poor prognosis in lung cancer patients. Restored FBP1 expression inhibited glucose uptake and lactate production, but induced oxygen consumption. Restored FBP1 expression also inhibited lung cancer cells proliferation and invasion under hypoxia in vitro, and inhibited lung cancer growth in vivo. Moreover, we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. Our findings indicate that the down-regulation of FBP1 is a critical oncogenic event in lung cancer progression.

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“…(55, 56) In addition to gene silencing, hypermethylation can also result in gene activation by inhibiting access of transcriptional repressors to a promoter’s regulatory regions. (57, 58) Hypermethylation of repressive sequences in the hTERT gene has been shown to upregulate hTERT expression in high-risk HPV induced cervical cancer. (59) Our data show that hypermethylation of CpG islands in the IL-15 promoter within CTCL patients’ CD4+ T-cells prevents the transcriptional repressor Zeb1 (also known as TCF8) from binding and negatively regulating IL-15 expression, thus providing an explanation for the overexpression of IL-15 in CTCL patients’ CD4+ T-cells and offering the first evidence for the epigenetic regulation of its expression.…”

Section: Discussionmentioning

confidence: 99%

Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma

et al. 2016

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Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here we report that CTCL patients show increased interleukin-15 (IL-15) in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 in T-cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6, and transcriptional induction of the onco-miR-21. Interruption of IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

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Defective binding of transcriptional repressor ZEB via DNA methylation contributes to increased constitutive levels of p73 in Fanconi anemia cells

Cited by 16 publications

References 16 publications

Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients

Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells

Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma

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