Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: EC:2.1.1.37 (
DNA methyltransferase
)
4,983
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Opioid binding protein/cell adhesion molecule-like gene (OPCML), a recently identified tumor-suppressor, is frequently inactivated by allele loss and CpG island promoter methylation in epithelial ovarian cancer. Since elevated activation of the RAS signaling pathway, including overexpression of HER-2/neu and mutations of RAS and BRAF, is common in human ovarian carcinoma, we examined the cellular effect of oncogenic RAS on the expression status of OPCML in a genetically defined human ovarian cancer model. Our study revealed that RAS(V12)-mediated oncogenic transformation was accompanied by a concomitant loss of OPCML expression. Methylation-sensitive PCR analysis showed that the OPCML promoter was hypermethylated in RAS-transformed human ovarian epithelial cells (T29H) and that treatment with the
DNA methyltransferase
inhibitor 5'-aza-2'-deoxycytidine promoted demethylation of the OPCML promoter and restored OPCML expression in T29H cells. Furthermore, suppression of oncogenic RAS activity by stable siRNA specific for
HRAS
(V12) led to the demethylation and re-expression of OPCML in T29H cells, demonstrating that oncogenic RAS activity is directly responsible for the observed OPCML promoter hypermethylation and epigenetic gene silencing of OPCML. Taken together, our study suggests that elevation of the RAS signaling pathway may play an important role in epigenetic inactivation of OPCML in human epithelial ovarian cancer.
...
PMID:RAS-mediated epigenetic inactivation of OPCML in oncogenic transformation of human ovarian surface epithelial cells. 1638 11
Hepatocellular carcinoma often reactivates the genes that are transiently expressed in fetal or neonatal livers. However, the mechanism of their activation has not been elucidated. To explore how oncogenic signaling pathways could be involved in the process, we examined the expression of fetal/neonatal genes in liver tumors induced by the introduction of myristoylated v-akt murine thymoma viral oncogene (AKT), HRas proto-oncogene, guanosine triphosphatase (
HRAS
V12
), and MYC proto-oncogene, bHLH transcription factor (Myc), in various combinations, into mouse hepatocytes
in vivo
. Distinct sets of fetal/neonatal genes were activated in
HRAS
- and
HRAS
/Myc-induced tumors: aldo-keto reductase family 1, member C18 (
Akr1c18
), glypican 3 (
Gpc3
), carboxypeptidase E (
Cpe
), adenosine triphosphate-binding cassette, subfamily D, member 2 (
Abcd2
), and trefoil factor 3 (
Tff3
) in the former; insulin-like growth factor 2 messenger RNA binding protein 3 (
Igf2bp3
), alpha fetoprotein (
Afp
),
Igf2
, and H19, imprinted maternally expressed transcript (
H19
) in the latter. Interestingly,
HRAS
/Myc-induced tumors comprised small cells with a high nuclear/cytoplasmic ratio and messenger RNA (mRNA) expression of delta-like noncanonical Notch ligand 1 (
Dlk1
), Nanog homeobox (
Nanog
), and sex determining region Y-box 2 (
Sox2
). Both
HRAS
- and
HRAS
/Myc-induced tumors showed decreased DNA methylation levels of
Line1
and
Igf2
differentially methylated region 1 and increased nuclear accumulation of 5-hydroxymethylcytosine, suggesting a state of global DNA hypomethylation.
HRAS
/Myc-induced tumors were characterized by an increase in the mRNA expression of enzymes involved in DNA methylation (
DNA methyltransferase
[
Dnmt1
,
Dnmt3
]) and demethylation (ten-eleven-translocation methylcytosine dioxygenase 1 [
Tet1
]), sharing similarities with the fetal liver. Although mouse hepatocytes could be transformed by the introduction of
HRAS
/Myc
in vitro
, they did not express fetal/neonatal genes and sustained global DNA methylation, suggesting that the epigenetic alterations were influenced by the
in vivo
microenvironment. Immunohistochemical analyses demonstrated that human hepatocellular carcinoma cases with nuclear MYC expression were more frequently positive for AFP, IGF2, and DLK1 compared with MYC-negative tumors.
Conclusion:
The
HRAS
signaling pathway and its interactions with the Myc pathway appear to reactivate fetal/neonatal gene expression in hepatocytic tumors partly through epigenetic alterations, which are dependent on the tumor microenvironment.
...
PMID:Emergence of the Dedifferentiated Phenotype in Hepatocyte-Derived Tumors in Mice: Roles of Oncogene-Induced Epigenetic Alterations. 3106 57
