Consequences of VHL Loss on Global DNA Methylome

Robinson, Claire M.; Lefebvre, François; Poon, Betty; Bousard, Aurélie; Fan, Xiaojun; Lathrop, Mark; Tost, Jörg; Kim, William Y.; Riazalhosseini, Yasser; Ohh, Michael

doi:10.1038/s41598-018-21524-5

Cited by 16 publications

(14 citation statements)

References 37 publications

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“…Our finding that epigenetic dysfunction is an obligate early event is likely to be generalizable to other forms of cancer. In renal cell carcinoma, loss of the tumor suppressor von Hippel-Lindau (VHL) is widely regarded as an initiating event and associated with dramatic changes in global DNA methylation, potentially impacting subsequently acquired signaling mutations 34 . In breast cancer, mutation order is an important determinant of cancer phenotype, with luminal-type tumors demonstrating early loss of PTEN while basal-type tumors display early p53 mutation 35 .…”

Section: Discussionmentioning

confidence: 99%

Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

et al. 2019

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Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

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Section: Discussionmentioning

confidence: 99%

Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

et al. 2019

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“…All values represent the mean ± SD. Asterisks indicate a significant difference (P < 0.05) binding of HIF-1α or HIF-2α and subsequently prevents the HIF-mediated transcription of HRE-containing genes [33]. Our results suggest that HRE motifs in FLT1 were methylated, suppressing the binding of HIF-α in all three choriocarcinoma cell lines, as sFLT1 production was enhanced by hypoxic stimulation after 5azadC treatment.…”

Section: Discussionmentioning

confidence: 66%

Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells

et al. 2020

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Background: Soluble Fms-like tyrosine kinase-1 (sFLT1) as an anti-angiogenic factor is abundantly expressed in placental trophoblasts. Choriocarcinoma, a malignant tumor derived from trophoblasts, is known to be highly angiogenic and metastatic. However, the molecular mechanism underlying angiogenesis in choriocarcinoma pathogenesis remains unclear. We aimed to investigate the mRNA expression and DNA methylation status of the FLT1 gene in human choriocarcinoma cells and trophoblast cells.Methods: qRT-PCR, Western blotting and ELISA were conducted to evaluate the mRNA and protein expression levels of sFLT1. 5-aza-2′-deoxycytidine (5azadC) treatment and bisulfite sequencing were used to study the FLT1 gene promoter methylation. The effect of sFLT1 on choriocarcinoma growth and angiogenesis was evaluated in a xenograft mouse model. Results: Expression of the FLT1 gene was strongly suppressed in choriocarcinoma cell lines compared with that in the primary trophoblasts. Treatment of choriocarcinoma cell lines with 5azadC, a DNA methyltransferase inhibitor, markedly increased in mRNA expression of three FLT1 splice variants and secretion of sFLT1 proteins. Bisulfite sequencing revealed that the CpG hypermethylation was observed at the FLT1 promoter region in choriocarcinoma cell lines and a human primary choriocarcinoma tissue but not in human trophoblast cells. Interestingly, in 5azadCtreated choriocarcinoma cell lines, sFLT1 mRNA expression and sFLT1 production were further elevated by hypoxic stimulation. Finally, as expected, sFLT1-expressing choriocarcinoma cells implanted into nude mice showed significantly slower tumor growth and reduced microvessel formation compared with GFP-expressing control choriocarcinoma cells.Conclusions: Inhibition of sFLT1 production by FLT1 silencing occurs via the hypermethylation of its promoter in choriocarcinoma cells. The stable expression of sFLT1 in choriocarcinoma cells resulted in the suppression of tumor growth and tumor vascularization in vivo. We suggest that the FLT1 gene may be a cell-type-specific tumor suppressor in choriocarcinoma cells.

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“…We recently discovered that HIF-2α, not HIF-1α, mediates the hypoxia-induced up-regulation of FLT1 expression in choriocarcinoma cell lines (BeWo, JAR, and JEG-3) and primary trophoblasts [21]. The HRE motif contains one CpG dinucleotide, and it has been confirmed that CpG methylation within this sequence prevents the binding of HIF-1α or HIF-2α and subsequently prevents the HIF-mediated transcription of HREcontaining genes [35]. Our results suggest that HRE motifs in FLT1 were methylated, suppressing the binding of HIF-α in all three choriocarcinoma cell lines, as sFLT1 production was enhanced by hypoxic stimulation after 5azadC treatment.…”

Section: Discussionmentioning

confidence: 99%

Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells

Sasagawa

Jinno-Oue

Nagamatsu

et al. 2020

Preprint

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Background: Soluble Fms-like tyrosine kinase-1 (sFLT1) as an anti-angiogenic factor is abundantly expressed in placental trophoblasts. Choriocarcinoma, a malignant tumor derived from trophoblasts, is known to be highly angiogenic and metastatic. However, the molecular mechanism underlying angiogenesis in choriocarcinoma pathogenesis remains unclear. We aimed to investigate the mRNA expression and DNA methylation status of the FLT1 gene in human choriocarcinoma cells and trophoblast cells. Methods: qRT-PCR, Western blotting and ELISA were conducted to evaluate the mRNA and protein expression levels of sFLT1. 5-aza-2'-deoxycytidine (5azadC) treatment and bisulfite sequencing were used to study the FLT1 gene promoter methylation. The effect of sFLT1 on choriocarcinoma growth and angiogenesis was evaluated in a xenograft mouse model. Results: Expression of the FLT1 gene was strongly suppressed in choriocarcinoma cell lines compared with that in the primary trophoblasts. Treatment of choriocarcinoma cell lines with 5azadC, a DNA methyltransferase inhibitor, markedly increased in mRNA expression of three FLT1 splice variants and secretion of sFLT1 proteins. Bisulfite sequencing revealed that the CpG hypermethylation was observed at the FLT1 promoter region in choriocarcinoma cell lines and a human primary choriocarcinoma tissue but not in human trophoblast cells. Interestingly, in 5azadC-treated choriocarcinoma cell lines, sFLT1 mRNA expression and sFLT1 production were further elevated by hypoxic stimulation. Finally, as expected, sFLT1-expressing choriocarcinoma cells implanted into nude mice showed significantly slower tumor growth and reduced microvessel formation compared with GFP-expressing control choriocarcinoma cells. Conclusions: Inhibition of sFLT1 production by FLT1 silencing occurs via the hypermethylation of its promoter in choriocarcinoma cells. The stable expression of sFLT1 in choriocarcinoma cells resulted in the suppression of tumor growth and tumor vascularization in vivo . We suggest that the FLT1 gene may be a cell-type-specific tumor suppressor in choriocarcinoma cells.

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Consequences of VHL Loss on Global DNA Methylome

Cited by 16 publications

References 37 publications

Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells

Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells

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